Methods and compositions for treating post-operative pain comprising a local anesthetic

ABSTRACT

The present invention is directed to an implantable drug depot useful for reducing, preventing or treating post-operative pain in a patient in need of such treatment, the implantable drug depot comprising a polymer and a therapeutically effective amount of a local anesthetic or pharmaceutically acceptable salt thereof, wherein the drug depot is implantable at a site beneath the skin to reduce, prevent or treat post-operative pain, and the drug depot is capable of releasing (i) a bolus dose of the local anesthetic or pharmaceutically acceptable salt thereof at a site beneath the skin and (ii) a sustained release dose of an effective amount of the local anesthetic or pharmaceutically acceptable salt thereof over a period of at least 4 days.

This application claims the benefit of the filing date of U.S.Provisional Application No. 61/046,343 filed Apr. 18, 2008 and entitled“Methods and Compositions for Treating Post-Operative Pain Comprising aLocal Anesthetic,” which is hereby incorporated by reference thereto.

BACKGROUND OF THE INVENTION

Pain relief is of prime importance to anyone treating patientsundergoing surgery. Proper pain relief imparts significant physiologicaland psychological benefits to the patient. Not only does effective painrelief mean a smoother more pleasant post-operative course (e.g., mood,sleep, quality of life, etc.) with earlier discharge frommedical/surgical/outpatient facilities, but it may also reduce the onsetof chronic pain syndromes (e.g., fibromyalgia, myalgia, etc.).

Pain serves a biological function. It often signals the presence ofdamage or disease within the body and is often accompanied byinflammation (redness, swelling, and/or burning). In the case ofpost-operative pain, it may be a result of the surgery, or othertreatments such as, for example, management of acute pain followingburns or non-surgical trauma. The goal for post-operative painmanagement is to reduce or eliminate pain and discomfort with medicationthat cause minimum or no side effects.

The site of the surgery has a profound effect upon the degree ofpost-operative pain a patient may suffer. In general, operations on thethorax and upper abdomen are more painful than operations on the lowerabdomen, which in turn are more painful than peripheral operations onthe limbs. However, any operation involving a body cavity, large jointsurfaces, the spine or deep tissues should be regarded as painful. Inparticular, operations on the thorax or upper abdomen may producewidespread changes in pulmonary function, an increase in abdominalmuscle tone and an associated decrease in diaphragmatic function. Theresult will be an inability to cough and clear secretions, which maylead to lung collapse and pneumonia. Prolonged pain can reduce physicalactivity and lead to venous stasis and an increased risk of deep veinthrombosis and consequently pulmonary embolism. In addition, there canbe widespread effects on gut and urinary tract motility, which may leadin turn to post-operative ileus, nausea, vomiting and urinary retention.These problems are unpleasant for the patient and may prolong hospitalstay. Most patients who experience moderate to severe post-operativepain, post-traumatic pain and burn pain, often require pain control atleast in the first 3 days after trauma or surgery.

One known class of pharmaceuticals to treat post-operative pain isopioids. This class of compounds is well-recognized as being among themost effective type of drugs for controlling post-operative pain.Unfortunately, because opioids are administered systemically, theassociated side effects raise significant concerns, including disablingthe patient, depressing the respiratory system, constipation, andpsychoactive effects such as sedation and euphoria, thereby institutinga hurdle to recovery and regained mobility. Further, because of theseside-effects, physicians typically limit the administration of opioidsto within the first 24 hours post-surgery. Thus, it would be preferableto use non-narcotic drugs that deliver direct, localized pain control ata surgical site.

One pharmaceutical that is known to the medical profession isbupivacaine, which is widely recognized as a local anesthetic forinfiltration, nerve block, epidural and intrathecal administration. Ingeneral, bupivacaine, also referred to as1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (C₁₈H₂₈N₂O) maybe represented by the following structure:

Because of the unique manifestation and relatively predictable risks forpost-operative pain, there is a need for effective treatments forpost-operative pain and/or inflammation, including methods andcompositions to alleviate and/or to treat post-operative pain and/orinflammation.

SUMMARY OF THE INVENTION

New compositions and methods are provided that effectively prevent,treat or reduce post-operative pain and/or inflammation. In variousembodiments, compositions and methods are provided that have long actinganalgesic and anti-inflammatory effects over periods of at least 4 daysin a single drug depot or multiple drug depots. New compositions andmethods are provided, which can easily allow accurate and preciseimplantation of a drug depot including an analgesic with minimalphysical and psychological trauma to a patient. The drug depot can nowbe easily delivered to the target tissue site (e.g., abdomen, synovialjoint, at or near the spinal column, etc.) and alleviate and/or treatpain for at least 4 to 10 days. In this way, accurate and preciseimplantation of the drug depot in a minimally invasive procedure can beaccomplished.

In one exemplary embodiment, an implantable drug depot useful forreducing, preventing or treating post-operative pain or inflammation ina patient in need of such treatment is provided. The implantable drugdepot comprises a therapeutically effective amount of an analgesic orpharmaceutically acceptable salt thereof and the depot is implantable ata site beneath the skin to reduce, prevent or treat post-operative pain.The drug depot is capable of releasing an effective amount of theanalgesic or pharmaceutically acceptable salt thereof over a period ofat least 4 days. The drug depot in the above embodiments may be capableof releasing (i) a bolus dose of the analgesic or local anesthetic orpharmaceutically acceptable salt thereof at a site beneath the skin and(ii) a sustained release dose of an effective amount of the analgesic orlocal anesthetic or pharmaceutically acceptable salt thereof over aperiod of at least 4 days. The drug depot may comprise a polymercomprising one or more of poly(lactide-co-glycolide), polylactide,polyglycolide, polyorthoester, D-lactide, D,L-lactide,poly(D,L-lactide), L-lactide, poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof. The polymer may be biodegradeable. The drug depotcan be a ribbon-like strip or fiber that releases the local anestheticover the period of at least 4 days. The drug depot can also be a gelformulation that releases the local anesthetic over the period of atleast 4 days.

In another exemplary embodiment, a method of making an implantable drugdepot is provided. The method comprises combining a biocompatiblepolymer and a therapeutically effective amount of local anesthetic orpharmaceutically acceptable salt thereof and forming the implantabledrug depot from the combination.

In yet another exemplary embodiment, a method of treating or preventingpost-operative pain or inflammation in a patient in need of suchtreatment is provided. The method comprises administering one or morebiodegradable drug depots comprising a therapeutically effective amountof an analgesic or pharmaceutically acceptable salt thereof to a targettissue site beneath the skin, wherein the drug depot releases aneffective amount of the analgesic or pharmaceutically acceptable saltthereof over a period of at least 4 days. The drug depot may be capableof releasing (i) a bolus dose of the analgesic or local anesthetic orpharmaceutically acceptable salt thereof at a site beneath the skin and(ii) a sustained release dose of an effective amount of the analgesic orlocal anesthetic or pharmaceutically acceptable salt thereof over aperiod of at least 4 days. The drug depot may comprise a polymercomprising one or more of poly(lactide-co-glycolide), polylactide,polyglycolide, polyorthoester, D-lactide, D,L-lactide,poly(D,L-lactide), L-lactide, poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof. The polymer may be biodegradeable. The drug depotcan be a ribbon-like strip that releases the local anesthetic over theperiod of at least 4 days. The drug depot can also be a gel formulationthat releases the local anesthetic over the period of at least 4 days.

In still yet another exemplary embodiment, a method of reducingpost-operative pain in a patient in need of such treatment is provided.The method comprises delivering one or more biodegradable drug depotscomprising a therapeutically effective amount of bupivacaine orpharmaceutically acceptable salt thereof to a target tissue site beneaththe skin before, during or after surgery, wherein the drug depot iscapable of releasing an initial bolus dose of an effective amount ofbupivacaine or pharmaceutically acceptable salt thereof at a sitebeneath the skin followed by a sustained release dose of an effectiveamount of bupivacaine or pharmaceutically acceptable salt thereof over aperiod of 4 to 30 days, 4 to 10 days, or 5 to 7 days. The drug depot maycomprise a polymer and the polymer may comprise one or more ofpoly(lactide-co-glycolide), polylactide, polyglycolide, polyorthoester,D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide,poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof. Bupivacaine may be in the form of a salt and/or inthe form of a base. The polymer may be biodegradeable. The drug depotmay be a ribbon-like strip. The drug depot is capable of releasing about40 to 90% of the bupivacaine or pharmaceutically acceptable salt thereofrelative to a total amount of bupivacaine or pharmaceutically acceptablesalt thereof loaded in the drug depot over the period of 4 to 10 daysafter the drug depot is administered to the target tissue site.

In yet another exemplary embodiment, an implantable drug depot usefulfor reducing, preventing or treating post-operative pain in a patient inneed of such treatment is provided. The implantable drug depot comprisesa therapeutically effective amount of bupivacaine or pharmaceuticallyacceptable salt thereof and a polymer. The depot is implantable at asite beneath the skin to reduce, prevent or treat post-operative pain.The depot is capable of releasing (i) about 2% to about 50% of thebupivacaine or pharmaceutically acceptable salt thereof relative to atotal amount of the bupivacaine or pharmaceutically acceptable saltthereof loaded in the drug depot over a first period of up to 48 hours,a first period of up to 24 hours, or a first period of about 24 to 48hours and (ii) about 50% to about 98% of the bupivacaine orpharmaceutically acceptable salt thereof relative to a total amount ofthe bupivacaine or pharmaceutically acceptable salt thereof loaded inthe drug depot over a subsequent period of up to 3 to 30 days, 2 to 10days or 3 to 10 days. The polymer comprises one or more ofpoly(lactide-co-glycolide), polylactide, polyglycolide, polyorthoester,D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide,poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof. The polymer may be biodegradeable. In variousembodiments, when the first period is up to 24 hours or about 24 to 48hours, the depot is capable of releasing about 2% to about 40% of thebupivacaine or pharmaceutically acceptable salt thereof.

In another exemplary embodiment, an implantable drug depot is provided.The implantable drug depot comprises: (i) a therapeutically effectiveamount of bupivacaine or pharmaceutically acceptable salt thereof; and(ii) a polymer. The depot is capable of releasing an initial bolus doseof bupivacaine or pharmaceutically acceptable salt thereof at a sitebeneath the skin, and the depot is capable of releasing a sustainedrelease dose of an effective amount of bupivacaine or pharmaceuticallyacceptable salt thereof over a subsequent period of 4 to 30 days or 4 to10 days. The drug depot is capable of releasing about 40% to about 70%of the bupivacaine or pharmaceutically acceptable salt thereof relativeto a total amount of bupivacaine loaded in the drug depot over thesustained release period of 4 to 30 days or 4 to 10 days after the drugdepot is administered. The polymer comprises one or more ofpoly(lactide-co-glycolide), polylactide, polyglycolide, polyorthoester,D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide,poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof.

In various embodiments, the analgesic may be a local anesthetic or apharmaceutically acceptable salt thereof and the local anesthetic may beat least one of bupivacaine, ropivacaine, mepivacaine, etidocaine,levobupivacaine, trimecaine, carticaine or articaine. Bupivacaine may bein the form of a salt and/or in the form of a base. The local anestheticor pharmaceutically acceptable salt thereof may be encapsulated in aplurality of depots comprising microparticles, microspheres,microcapsules, and/or microfibers suspended in a gel.

In various embodiments, the drug depot may comprise a polymer andfurther an excipient. In particular, the drug depot may comprise a localanesthetic in an amount of about 30 to about 90 weight percent (wt. %),about 10 to about 80 wt. % of a polymer and about 0.5 to about 20 wt. %of an excipient. For example, the drug depot can include a localanesthetic at an amount of about 30 to about 90 wt. % of the implantabledrug depot, about 10 to about 80 wt. % PLGA and about 0.5 to about 20wt. % mPEG.

The drug depot in various embodiments is capable of releasing aneffective amount of the analgesic or pharmaceutically acceptable saltthereof over a period of at least 4 days. For example, the drug depotmay release about 40% to about 70% of the analgesic or local anestheticor pharmaceutically acceptable salt thereof relative to a total amountof the analgesic or local anesthetic loaded in the drug depot over aperiod of 4 to 10 days after the drug depot is administered to a targettissue site. The analgesic or local anesthetic is released in an amountbetween 50 and 800 mg per day during this period of 4 to 10 days. Thedrug depot, though, is capable of releasing an effective amount of theanalgesic or local anesthetic or pharmaceutically acceptable saltthereof over a much greater period, e.g., at least 7 days and in therange of 7 to 30 days, after the drug depot is administered to the site.

The polymer(s) in various embodiments may comprise about 10% to about70% of the total wt. % of the drug depot or about 15% to about 55% ofthe total wt. % of the drug depot. The polymer(s) is capable ofdegrading or degrades in 30 days or less after the drug depot isimplanted at the site.

The drug depot in various embodiments may comprise a radiographic markeradapted to assist in radiographic imaging. The radiographic marker maycomprise barium, calcium phosphate, and/or metal beads.

The drug depot in various embodiments may comprise at least oneadditional anti-inflammatory or analgesic agent, at least one anabolicor an anti-catabolic growth factor or a combination thereof.

The drug depot is capable of releasing or releases between 0.5 and 1,000mg/day of the analgesic or local anesthetic including bupivacaine or apharmaceutically acceptable salt thereof to reduce post-operative pain.

In various embodiments, bupivacaine may be in the form of a salt orbase. Further, bupivacaine or a pharmaceutically acceptable salt thereofmay be encapsulated in a plurality of depots comprising microparticles,microspheres, microcapsules, and/or microfibers suspended in a gel. Thedrug depot may be a ribbon-like strip or a gel formulation.

The target tissue site comprises at least one muscle, ligament, tendon,cartilage, spinal disc, spinal foraminal space near the spinal nerveroot, facet or synovial joint, or spinal canal.

The pain may be associated with hernia repair, orthopedic or spinesurgery or a combination thereof. The surgery may be arthroscopicsurgery, an excision of a mass, hernia repair, spinal fusion, thoracic,cervical, or lumbar surgery, pelvic surgery or a combination thereof.

One or more drug depots of the present invention may be used to treatconditions of pain and/or inflammation in chronic conditions includingrheumatoid arthritis, osteoarthritis, sciatica, carpal tunnel syndrome,lower back pain, lower extremity pain, upper extremity pain, cancer,tissue pain and pain associated with injury or repair of cervical,thoracic, and/or lumbar vertebrae or intervertebral discs, rotator cuff,articular joint, TMJ, tendons, ligaments, muscles, or the like.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 illustrates a number of common locations such as knees 21, hips22, fingers 23, thumbs 24, neck 25, and spine 26 within a patient thatmay be sites where surgery is conducted and locations where the drugdepot containing an analgesic or local anesthetic can be administeredthereto.

FIG. 2 illustrates a schematic dorsal view of the spine and sites wherea drug depot containing an analgesic or local anesthetic can beadministered thereto beneath the skin 34 to a spinal site 30 (e.g.,spinal disc space, spinal canal, soft tissue surrounding the spine,nerve root, etc.) and one or more drug depots 28 and 32 are delivered tovarious sites along the spine.

FIG. 3 is a graphic representation of the average percentage cumulativerelease of bupivacaine formulations from Example 1.

FIG. 4 is a graphic representation of the average cumulative dailyrelease in milligrams for the bupivacaine formulations from Example 1.

FIG. 5 is a graphic representation of the efficacy data from in vivotesting of bupivacaine formulations from Example 1.

FIG. 6 is a graphic representation of the efficacy data from in vivotesting of bupivacaine formulations from Example 1.

FIG. 7 is a graphic representation of a study of the average cumulativerelease in ug of bupivacaine sterilized POP implants described inExample 2. (POP refers to post-operative pain).

FIG. 8 is a graphic representation of a study of the average percentagecumulative release of sterilized bupivacaine POP implants described inExample 2.

FIG. 9 is a graphic representation of the thermal paw withdrawalthreshold in grams per days post-surgery for bupivacaine implants fromExample 2.

FIG. 10 is a graphic representation of the average cumulative in vitrorelease profile for bupivacaine formulations from a study described inExample 4.

FIG. 11 is a graphic representation of the average cumulative in vitrorelease profile for bupivacaine formulations from a study described inExample 4.

FIG. 12 is a graphic representation of the average cumulative in vitrorelease profile for another bupivacaine formulation from a studydescribed in Example 4.

FIG. 13 is a graphic representation of the average cumulative in vitrorelease profile for bupivacaine implants from a study described inExample 5.

FIG. 14 is a graphic representation of the average cumulative in vitrorelease profile for bupivacaine implants from a study described inExample 5.

FIG. 15A is a graphic representation of the percentage cumulativerelease for three bupivacaine strips from a study described in Example6.

FIG. 15B is a graphic representation of the average percentagecumulative release for the bupivacaine strips shown in FIG. 15A.

FIG. 16A is a graphic representation of the cumulative in vitro releasein ug for the three bupivacaine strips described in Example 6.

FIG. 16B is a graphic representation of the average cumulative in vitrorelease in ug for the bupivacaine strips shown in FIG. 16B.

FIG. 17 is a graphic representation of pain scores of bupivacaine depotsimplanted post-operatively at the surgical incision.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents, which may be included within the invention as defined bythe appended claims.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

New compositions and methods are provided that effectively prevent,treat or reduce post-operative pain or inflammation. In variousembodiments, compositions and methods are provided that have long actinganalgesic and anti-inflammatory effects over periods of at least 4 daysin a single drug depot or multiple drug depots. New analgesiccompositions and methods are provided, which can easily allow accurateand precise implantation of a drug depot including an analgesic such asbupivacaine with minimal physical and psychological trauma to a patient.The drug depot can now be easily delivered to the target tissue site(e.g., abdomen, synovial joint, at or near the spinal column, etc.) andalleviate and/or treat pain for at least 4 to 10 days. In this way,accurate and precise implantation of the drug depot in a minimallyinvasive procedure as well as an open procedure can be accomplished.

Bupivacaine

Bupivacaine or another local anesthetic may be contained in a drugdepot. A drug depot comprises a physical structure to facilitateimplantation and retention in a desired site (e.g., a synovial joint, adisc space, a spinal canal, abdominal area, a tissue of the patient,etc.). The drug depot also comprises the drug. The term “drug” as usedherein is generally meant to refer to any substance that alters thephysiology of a patient. The term “drug” may be used interchangeablyherein with the terms “therapeutic agent”, “therapeutically effectiveamount”, and “active pharmaceutical ingredient” or “API”. It will beunderstood that a “drug” formulation may include more than onetherapeutic agent, wherein exemplary combinations of therapeutic agentsinclude a combination of two or more drugs. The drug depot provides aconcentration gradient of the therapeutic agent for delivery to thesite. In various embodiments, the drug depot provides an optimal drugconcentration gradient of the therapeutic agent at a distance of up toabout 1 cm to about 10 cm from the implant site.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition of inflammation, reduction oralleviation of pain, improvement in the condition, etc. In variousembodiments, the therapeutically effective amount of bupivacainecomprises from about 0.5 mg to 1,000 mg/day. In some embodiments, thetherapeutically effective amount of bupivacaine comprises from about 0.1mg to 800 mg of bupivacaine per day. In some embodiments, thetherapeutically effective amount of bupivacaine comprises from about 50mg to 800 mg of bupivacaine per day or from about 200 mg to 800 mg ofbupivacaine per day. In some embodiments, the therapeutically effectiveamount of bupivacaine comprises about 0.5 mg, 100 mg, 200 mg, 300 mg,400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1,000 mg ofbupivacaine per day and all subranges therebetween. In some embodiments,the therapeutically effective amount of bupivacaine comprises 0.5 mg,0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg,1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg,18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 30 mg, 35 mg, or40 mg of bupivacaine per day. In one embodiment, the dosage to a humanis between 400 mg and 600 mg of bupivacaine per day. It will beunderstood that the dosage administered to a patient can be as singledepot or multiple depots depending upon a variety of factors, includingthe drug's administered pharmacokinetic properties, the route ofadministration, patient conditions and characteristics (sex, age, bodyweight, health, size, etc.), extent of symptoms, concurrent treatments,frequency of treatment and the effect desired. For example, lower dailydoses of bupivacaine may be needed when there is concurrent treatmentwith an opioid (e.g., morphine), alternatively, the patient may requirehigher doses of bupivacaine as the dosage of the opioid (e.g., morphine)is reduced or eliminated to control post-operative pain.

In various embodiments, a therapeutically effective amount ofbupivacaine is provided to inhibit, treat and/or prevent post-operativepain or inflammation. In general, the chemical name of bupivacaine is1-butyl-N-(2,6-dimethylphenyl) piperidine-2-carboxamide. Bupivacaine hasa molecular weight of 288.43 and exhibits the following generalstructure:

Bupivacaine includes, but is not limited to,(±)-1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide orpharmaceutically acceptable non-toxic esters or salts thereof.Bupivacaine includes the racemic mixtures ((+)-R and (−)-S enantiomers)or each of the dextro and levo isomers of bupivacaine individually.Bupivacaine includes the free acid as well as any other pharmaceuticallyacceptable salt of any one of the foregoing. Bupivacaine may also bepegylated for long acting activity.

Pharmaceutically acceptable esters of bupivacaine include but are notlimited to, alkyl esters derived from hydrocarbons of branched orstraight chain having one to about 12 carbon atoms. Examples of suchesters are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isoamyl,pentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl ordodecyl esters.

Pharmaceutically acceptable salts of bupivacaine include salts derivedfrom either inorganic or organic bases. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, ferrous, zinc, copper, manganese,aluminum, ferric, manganic salts or the like. Salts derived frompharmaceutically acceptable organic non-toxic bases include, but are notlimited to, salts of primary, secondary, or tertiary amines, substitutedamines including naturally occurring substituted amines or cyclic aminesor basic ion exchange resins, such as isopropylamine, trimethylamine,diethylamine, triethylamine, tripropylamine, ethanolamine,2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins or the like.

In addition to bupivacaine, the drug depot may comprise one or moreadditional therapeutic agents. Examples of therapeutic agents include,those that are direct- and local-acting modulators of pro-inflammatorycytokines such as TNF-α and IL-1 including, but not limited to, solubletumor necrosis factor α receptors, any pegylated soluble tumor necrosisfactor α receptor, monoclonal or polyclonal antibodies or antibodyfragments or combinations thereof. Examples of suitable therapeuticagents include receptor antagonists, molecules that compete with thereceptor for binding to the target molecule, antisense polynucleotides,and inhibitors of transcription of the DNA encoding the target protein.Suitable examples include but are not limited to Adalimumab, Infliximab,Etanercept, Pegsunercept (PEG sTNF-R1), sTNF-R1, CDP-870, CDP-571,CNI-1493, RDP58, ISIS 104838, 1→3-β-D-glucans, Lenercept, PEG-sTNFRII FcMutein, D2E7, Afelimomab, and combinations thereof. In otherembodiments, a therapeutic agent includes metalloprotease inhibitors,glutamate antagonists, glial cell-derived neurotropic factors (GDNF), B2receptor antagonists, Substance P receptor (NK1) antagonists such ascapsaicin and civamide, downstream regulatory element antagonisticmodulator (DREAM), iNOS, inhibitors of tetrodotoxin (TTX)-resistantNa+-channel receptor subtypes PN3 and SNS2, inhibitors of interleukinssuch as IL-1, IL-6 and IL-8, and anti-inflammatory cytokines, TNFbinding protein, onercept (r-hTBP-1), recombinant adeno-associated viral(rAAV) vectors encoding inhibitors, enhancers, potentiators, orneutralizers, antibodies, including but not limited to naturallyoccurring or synthetic, double-chain, single-chain, or fragmentsthereof. For example, suitable therapeutic agents include molecules thatare based on single chain antibodies called Nanobodies™ (Ablynx, GhentBelgium), which are defined as the smallest functional fragment of anaturally occurring, single-domain antibody. Alternatively, therapeuticagents include, agents that effect kinases and/or inhibit cell signalingmitogen-activated protein kinases (MAPK), p38 MAPK, Src or proteintyrosine kinase (PTK). Therapeutic agents include, kinase inhibitorssuch as, for example, Gleevec, Herceptin, Iressa, imatinib (ST1571),herbimycin A, tyrphostin 47, erbstatin, genistein, staurosporine,PD98059, SB203580, CNI-1493, VX-50/702 (Vertex/Kissei), SB203580, BIRB796 (Boehringer Ingelheim), Glaxo P38 MAP Kinase inhibitor, RWJ67657(J&J), U0126, Gd, SCIO-469 (Scios), RO3201195 (Roche), Semipimod(Cytokine PharmaSciences), or derivatives thereof.

Therapeutic agents, in various embodiments, block the transcription ortranslation of TNF-α or other proteins in the inflammation cascade.Suitable therapeutic agents include, but are not limited to, integrinantagonists, alpha-4 beta-7 integrin antagonists, cell adhesioninhibitors, interferon gamma antagonists, CTLA4-Ig agonists/antagonists(BMS-188667), CD40 ligand antagonists, Humanized anti-IL-6 mAb (MRA,Tocilizumab, Chugai), HMGB-1 mAb (Critical Therapeutics Inc.), anti-IL2Rantibodies (daclizumab, basilicimab), ABX (anti IL-8 antibodies),recombinant human IL-10, or HuMax IL-15 (anti-IL 15 antibodies).

Other suitable therapeutic agents include IL-1 inhibitors, such Kineret®(anakinra) which is a recombinant, non-glycosylated form of the humaninerleukin-1 receptor antagonist (IL-1Ra), or AMG 108, which is amonoclonal antibody that blocks the action of IL-1. Therapeutic agentsalso include excitatory amino acids such as glutamate and aspartate,antagonists or inhibitors of glutamate binding to NMDA receptors, AMPAreceptors, and/or kainate receptors. Interleukin-1 receptor antagonists,thalidomide (a TNF-α release inhibitor), thalidomide analogues (whichreduce TNF-α production by macrophages), bone morphogenetic protein(BMP) type 2 and BMP-4 (inhibitors of caspase 8, a TNF-α activator),quinapril (an inhibitor of angiotensin II, which upregulates TNF-α),interferons such as IL-11 (which modulate TNF-α receptor expression),and aurin-tricarboxylic acid (which inhibits TNF-α), for example, mayalso be useful as therapeutic agents for reducing inflammation. It iscontemplated that where desirable a pegylated form of the above may beused. Examples of other therapeutic agents include NF kappa B inhibitorssuch as glucocorticoids, clonidine; antioxidants, such asdithiocarbamate, and other compounds, such as, for example,sulfasalazine.

Specific examples of therapeutic agents suitable for use include, butare not limited to an anti-inflammatory agent, analgesic agent, orosteoinductive growth factor or a combination thereof. Anti-inflammatoryagents include, but are not limited to, salicylates, diflunisal,sulfasalazine, indomethacin, ibuprofen, naproxen, tolmetin, diclofenac,ketoprofen, fenamates (mefenamic acid, meclofenamic acid), enolic acids(piroxicam, meloxicam), nabumetone, celecoxib, etodolac, nimesulide,apazone, gold, sulindac or tepoxalin; antioxidants, such asdithiocarbamate, and other compounds such as sulfasalazine[2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoic acid],steroids, such as fluocinolone, cortisol, cortisone, hydrocortisone,fludrocortisone, prednisone, prednisolone, methylprednisolone,triamcinolone, betamethasone, dexamethasone, beclomethasone, fluticasoneor a combination thereof.

Suitable anabolic growth or anti-catabolic growth factors include, butare not limited to, a bone morphogenetic protein, a growthdifferentiation factor, a LIM mineralization protein, CDMP or progenitorcells or a combination thereof.

Additional analgesic agents may also be included in the depot. Suitableanalgesic agents include, but are not limited to, acetaminophen,lidocaine, opioid analgesics such as buprenorphine, butorphanol,dextromoramide, dezocine, dextropropoxyphene, diamorphine, fentanyl,alfentanil, sufentanil, hydrocodone, hydromorphone, ketobemidone,levomethadyl, mepiridine, methadone, morphine, nalbuphine, opium,oxycodone, papaveretum, pentazocine, pethidine, phenoperidine,piritramide, dextropropoxyphene, remifentanil, tilidine, tramadol,codeine, dihydrocodeine, meptazinol, dezocine, eptazocine, flupirtine ora combination thereof.

Suitable analgesics also include agents with analgesic properties, suchas for example, amitriptyline, carbamazepine, gabapentin, pregabalin,clonidine, or a combination thereof.

The depot may contain a muscle relaxant. Exemplary muscle relaxantsinclude by way of example and not limitation, alcuronium chloride,atracurium bescylate, baclofen, carbolonium, carisoprodol, chlorphenesincarbamate, chlorzoxazone, cyclobenzaprine, dantrolene, decamethoniumbromide, fazadinium, gallamine triethiodide, hexafluorenium,meladrazine, mephensin, metaxalone, methocarbamol, metocurine iodide,pancuronium, pridinol mesylate, styramate, suxamethonium, suxethonium,thiocolchicoside, tizanidine, tolperisone, tubocuarine, vecuronium, orcombinations thereof.

The depot comprises the therapeutic agent or agents and may also containother non-active ingredients. These non-active ingredients may have amulti-functional purpose including the carrying, stabilizing andcontrolling of the release of the therapeutic agent(s). The sustainedrelease process, for example, may be by a solution-diffusion mechanismor it may be governed by an erosion-controlled process. Typically, thedepot will be a solid or semi-solid formulation comprised of abiocompatible material, which can be biodegradable. The term “solid” isintended to mean a non-gel like material, while, “semi-solid” isintended to mean a gel like material that has some degree offlowability, thereby allowing the depot to bend and conform to thesurrounding tissue requirements. The term “gel” is intended to mean amaterial that is soft and deformable at any point in its application tothe surgical site.

In various embodiments, the depot material will be durable within thetissue site for a period of time similar to (for biodegradablecomponents) or greater than (for non-biodegradable components) theplanned period of drug delivery. For example, the depot material mayhave a melting point or glass transition temperature close to or higherthan body temperature, but lower then the decomposition or degradationtemperature of the therapeutic agent. However, the pre-determinederosion of the depot material can also be used to provide for slowrelease of the loaded therapeutic agent(s).

In various embodiments, the drug depot may be designed to release thelocal anesthetic such as bupivacaine when certain trigger points arereached (e.g., temperature, pH, etc.) after implantation in vivo. Forexample, the drug depot may comprise polymers that will release moredrug as the body temperature reaches greater than, for example, 102° F.,particularly if the drug possesses antipyretic properties. In variousembodiments, depending on the site of implantation, the drug depot mayrelease more or less drug as a certain pH is reached. For example, thedrug depot may be designed to release the drug as the bodily fluidhaving a certain pH contact the drug depot (e.g., CSF having a pH ofabout 7.35 to about 7.70, synovial fluid having a pH of about 7.29 toabout 7.45; urine having a pH of about 4.6 to about 8.0, pleural fluidshaving a pH of about 7.2 to about 7.4, blood having a pH of about 7.35to about 7.45, etc.).

In various embodiments, the depot may have a high drug loading, suchthat the local anesthetic such as bupivacaine and/or other therapeuticagent comprises about 5-99 wt. % of the depot, or 30-95 wt. % of thedepot, 30-90 wt. % of the depot, or 50-75 wt. % of the depot, or 55-65wt. % of the depot. In various embodiments, the amount of bupivacaineand/or other therapeutic agent are present in the depot in a range fromabout 40% to about 80% by weight of the depot (including 40%, 41%, 42%,43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%,71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, and any ranges betweenany two of these points, for instance, 40.1-50%, 50-60% and 60-70%,etc.).

In various embodiments, the drug depot may release 0.1 mg, 0.2 mg, 0.3mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg 1.8 mg, 1.9 mg, 2 mg, 3 mg, 4mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25mg, 30 mg, 35 mg, or 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg,120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg,165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 300 mg,400 mg, 500 mg, 600 mg, 700 mg 800 mg, 900 mg, or 1,000 mg ofbupivacaine per day and all subranges therebetween for a total of atleast 4 days, at least 7 days, at least 8 days, 4 to 30 days, 4 to 10days, 4 to 8 days, 5 to 7 days, or 7 to 10 days. In various embodiments,the drug depot may release 0.5 mg to 20 mg of bupivacaine per hour for atotal of at least 4 days, 4 to 10 days, 5 to 7 days or 7 to 10 days toreduce, treat or prevent post-operative pain. In various embodiments,the drug depot releases 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%,55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% of thebupivacaine over a period of 3 to 10 days, 4 to 10 days, or 5 to 7 daysafter the drug depot is administered to the target tissue site. The drugdepot may have a “release rate profile” that refers to the percentage ofactive ingredient that is released over fixed units of time, e.g.,mg/hr, mg/day, 10% per day for ten days, etc. As persons of ordinaryskill know, a release rate profile may be but need not be linear. By wayof a non-limiting example, the drug depot may be a strip or aribbon-like strip or fiber that releases the bupivacaine over a periodof time.

In various embodiments, the drug depot comprises from about 40% to 80%by weight bupivacaine, 15% to 55% by weight of a polymer and 5% to 15%by weight of an excipient. mPEG may be used as an excipient orplasticizer for a polymer as it imparts malleability to the resultingformulation. PEG 300 may also be used as an excipient. In addition, acombination of PEG 300 and NMP may be used as the excipient.

Exemplary excipients that may be formulated with bupivacaine in additionto the biodegradable polymer include but are not limited to MgO (e.g., 1wt. %), 5050 DLG 6E, 5050 DLG 1A, mPEG, TBO-Ac, mPEG, Span-65, Span-85,pluronic F127, TBO-Ac, sorbital, cyclodextrin, maltodextrin andcombinations thereof. In some embodiments, the excipient or excipientsmay comprise from about 0.001 wt. % to about 50 wt. % of theformulation. In some embodiments, the excipient(s) comprise from about0.001 wt. % to about 40 wt. % of the formulation. In some embodiments,the excipient(s) comprise from about 0.001 wt. % to about 30 wt. % ofthe formulation. In some embodiments, the excipient(s) comprise fromabout 0.001 wt. % to about 20 wt. % of the formulation. In someembodiments, the excipient(s) comprise from about 0.5 wt. % to about 20wt. % of the formulation. In some embodiments, the excipient(s) comprisefrom about 0.001 wt. % to about 10 wt. % of the formulation. In someembodiments, the excipient(s) comprise from about 0.001 wt. % to about 2wt. % of the formulation.

In some embodiments, the drug depot may not be biodegradable. Forexample, the drug depot may comprise polyurethane, polyurea,polyether(amide), PEBA, thermoplastic elastomeric olefin, copolyester,and styrenic thermoplastic elastomer, steel, aluminum, stainless steel,titanium, metal alloys with high non-ferrous metal content and a lowrelative proportion of iron, carbon fiber, glass fiber, plastics,ceramics or combinations thereof. Typically, these types of drug depotsmay need to be removed after a certain amount of time.

In some instances, it may be desirable to avoid having to remove thedrug depot after use. In those instances, the drug depot may comprise abiodegradable material. There are numerous materials available for thispurpose and having the characteristic of being able to breakdown ordisintegrate over a prolonged period of time when positioned at or nearthe target tissue. As function of the chemistry of the biodegradablematerial the mechanism of the degradation process can be hydrolytical orenzymatical in nature, or both. In various embodiments, the degradationcan occur either at the surface (heterogeneous or surface erosion) oruniformly throughout the drug delivery system depot (homogeneous or bulkerosion).

The drug depot may comprise a polymeric or non-polymeric material aswell as a synthetic or naturally occurring material, or a combinationthereof. Non-polymeric materials include, for example, cholesterol,stigmasterol, glycerol, estradiol, sucrose, distearate, sorbitan,sorbitan monooleate, sorbitan monopalmitate, sorbitan tristearate, orthe like.

In various embodiments, the drug depot comprises a polymer and thepolymer will degrade in vivo over a period of less than a year, with atleast 50% of the polymer degrading within six months or less. In someembodiments, the polymer is capable of or will degrade in two months,one month or less. In some embodiments, the polymer will degradesignificantly within a month, with at least 50% of the polymer degradinginto non-toxic residues which are removed by the body, and 100% of thedrug being released within a two week period. Polymers should alsodegrade by hydrolysis by surface erosion, rather than by bulk erosion,so that release is not only sustained but also linear. Polymers whichmeet this criteria include some of the polyanhydrides, co-polymers oflactic acid and glycolic acid wherein the weight ratio of lactic acid toglycolic acid is no more than 4:1 (i.e., 80% or less lactic acid to 20%or more glycolic acid by weight), and polyorthoesters containing acatalyst or degradation enhancing compound, for example, containing atleast 1% by weight anhydride catalyst such as maleic anhydride. Otherpolymers include protein polymers such as gelatin and fibrin andpolysaccharides such as hyaluronic acid.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, sheets, strips, ribbon-like strips or fibers, mesh,a paste, a slab, pellets, gels, or other pharmaceutical deliverycompositions. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof.

The term “biodegradable” includes that all or parts of the drug depotwill degrade over time by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that the depot (e.g.,microparticle, microsphere, gel, etc.) can break down or degrade withinthe body to non-toxic components after or while a therapeutic agent hasbeen or is being released. By “bioerodible,” it is meant that the depotand/or gel will erode or degrade over time due, at least in part, tocontact with substances found in the surrounding tissue, fluids or bycellular action. By “bioabsorbable,” it is meant that the depot will bebroken down and absorbed within the human body, for example, by a cellor tissue. “Biocompatible” means that the depot will not causesubstantial tissue irritation or necrosis at the target tissue site.

In various embodiments, the depot may comprise a bioabsorbable, abioabsorbable, and/or a biodegradable biopolymer that may provideimmediate release, sustained release or controlled release of the drug.Examples of suitable sustained release biopolymers include but are notlimited to poly(alpha-hydroxy acids), poly(lactide-co-glycolide) (PLGAor DLG) (which includes poly(lactide-co-glycolide),poly(D-lactide-co-glycolide), poly(L-lactide-co-glycolide) andpoly(D,L-lactide-co-glycolide), polylactide (PLA), polyglycolide (PG),polyorthoester(s) (POE), polyethylene glycol (PEG), PEG 200, PEG 300,PEG 400, PEG 500, PEG 550, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000,PEG 1450, PEG 3350, PEG 4500, PEG 8000, conjugates of poly(alpha-hydroxyacids), polyaspirins, polyphosphagenes, collagen, starch,pre-gelatinized starch, hyaluronic acid, chitosans, gelatin, alginates,albumin, fibrin, vitamin E analogs, such as alpha tocopheryl acetate,d-alpha tocopheryl succinate, D-lactide, D,L-lactide, L-lactide,D,L-lactide-caprolactone (DL-CL), D,L-lactide-glycolide-caprolactone(DL-G-CL), dextrans, vinylpyrrolidone, polyvinyl alcohol (PVA),PVA-g-PLGA, PEGT-PBT copolymer (polyactive), methacrylates,poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics), PEO-PPO-PAAcopolymers, PLGA-PEO-PLGA, PEG-PLG, PLA-PLGA, poloxamer 407,PEG-PLGA-PEG triblock copolymers, SAIB (sucrose acetateisobutyrate)hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl methylcellulose, carboxymethylcellulose or salts thereof,Carbopol, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, or combinations thereof.

In various embodiments, the molecular weight of the polymer can be awide range of values. The average molecular weight of the polymer can befrom about 1000 to about 10,000,000; or about 1,000 to about 1,000,000;or about 5,000 to about 500,000; or about 10,000 to about 100,000; orabout 20,000 to 50,000.

In some embodiments, the polymer comprises PLGA or POE or a combinationthereof. The PLGA may comprise a mixture of polyglycolide andpolylactide and in some embodiments, in the mixture, there is morepolylactide than polyglycolide. In various embodiments, the PLGA maycomprise: 100% polylactide and 0% polyglycolide; 95% polylactide and 5%polyglycolide; 90% polylactide and 10% polyglycolide; 85% polylactideand 15% polyglycolide; 80% polylactide and 20% polyglycolide; 75%polylactide and 25% polyglycolide; 70% polylactide and 30%polyglycolide; 65% polylactide and 35% polyglycolide; 60% polylactideand 40% polyglycolide; 55% polylactide and 45% polyglycolide; 50%polylactide and 50% polyglycolide; 45% polylactide and 55%polyglycolide; 40% polylactide and 60% polyglycolide; 35% polylactideand 65% polyglycolide; 30% polylactide and 70% polyglycolide; 25%polylactide and 75% polyglycolide; 20% polylactide and 80%polyglycolide; 15% polylactide and 85% polyglycolide; 10% polylactideand 90% polyglycolide; 5% polylactide and 95% polyglycolide; or 0%polylactide and 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide,there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer ispolyglycolide.

In various embodiments, when the drug depot comprises a polymer, it isemployed at about 10 wt. % to about 90 wt. %, about 10 wt. % to about 80wt. %, about 10 wt. % to about 70 wt. %, about 10 wt. % to about 50 wt.%, or about 20 wt. % to about 40 wt. % based on the weight of the drugdepot.

In some embodiments, at least 75% of the particles have a size fromabout 1 micrometer to about 200 micrometers. In some embodiments, atleast 85% of the particles have a size from about 1 micrometer to about200 micrometers. In some embodiments, at least 95% of the particles havea size from about 1 micrometer to about 200 micrometers. In someembodiments, all of the particles have a size from about 1 micrometer toabout 200 micrometers.

In some embodiments, at least 75% of the particles have a size fromabout 20 micrometer to about 100 micrometers. In some embodiments, atleast 85% of the particles have a size from about 20 micrometers toabout 100 micrometers. In some embodiments, at least 95% of theparticles have a size from about 20 micrometer to about 100 micrometers.In some embodiments, all of the particles have a size from about 20micrometer to about 100 micrometers.

In some embodiments, the polymer comprises DL-CL or a combinationthereof. The DL-CL may comprise a mixture of lactide and caprolactone.The molar ratio of lactide to caprolactone can be 10:90 to 90:10 and allsubranges therebetween (e.g., 20:80, 30:70, 45:55, 65:35, 67:33, 89:11,etc.).

In some embodiments, the polymer comprises DL-G-CL or a combinationthereof. The DL-G-CL may comprise a mixture of lactide, glycolide andcaprolactone. In some embodiments, the molar ratio of lactide toglycolide to caprolactone may be 30:20:50. In some embodiments, themixture may comprise 5-50% lactide, 5-50% glycolide, and 20-80%caprolactone.

In various embodiments, when the drug depot comprises a polymer, it maybe employed at about 10 wt. % to about 90 wt. %, about 15 wt. % to about55 wt. %, about 25 wt. % to about 45 wt. %, or about 30 wt. % to about35 wt. % based on the weight of the drug depot.

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfite,sodium bisulfate, sodium thiosulfate, thimerosal, methyl and otherparaben, polyvinyl alcohol and phenylethyl alcohol; solubility adjustingagents; stabilizers; and/or cohesion modifiers. Typically, any suchinactive materials will be present within the range of 0-75 wt. %, andmore typically within the range of 0-30 wt. %. If the depot is to beplaced in the spinal area or joint area, in various embodiments, thedepot may comprise sterile preservative free material.

The depot can be different sizes, shapes and configurations. There areseveral factors that can be taken into consideration in determining thesize, shape and configuration of the drug depot. For example, both thesize and shape may allow for ease in positioning the drug depot at thetarget tissue site that is selected as the implantation or injectionsite. In addition, the shape and size of the system should be selectedso as to minimize or prevent the drug depot from moving afterimplantation or injection. In various embodiments, the drug depot can beshaped like a sphere, a cylinder such as a rod or fiber, a flat surfacesuch as a disc, film, ribbon, strip or sheet, a paste, a slab,microparticles, nanoparticles, pellets, mesh or the like. Flexibilitymay be a consideration so as to facilitate placement of the drug depot.In various embodiments, the drug depot can be different sizes, forexample, the drug depot may be a length of from about 0.5 mm to 100 mmand have a diameter or thickness of from about 0.01 to about 5 mm. Invarious embodiments, the drug depot may have a layer thickness of fromabout 0.005 to 5.0 mm, such as, for example, from 0.05 to 2.0 mm. Insome embodiments, the shape may be a strip or a ribbon-like strip andthe strip or ribbon-like strip has a ratio of width to thickness in therange of 2 to 20 or greater.

Radiographic markers can be included on or in the drug depot to permitthe user to accurately position the depot into the target site of thepatient. These radiographic markers will also permit the user to trackmovement and degradation of the depot at the site over time. In thisembodiment, the user may accurately position the depot in the site usingany of the numerous diagnostic imaging procedures. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.Examples of such radiographic markers include, but are not limited to,barium, calcium, and/or metal beads or particles. Where present, theradiographic marker is typically present in an amount of from about 10%to about 40% (including 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%,33%, 34%, 35%, 36%, 37%, 38%, 39% and 40%, as well as ranges between anytwo of these values, e.g., 10-15%, 15-20%, 20-25%, 25-30%, 30-35%,35-40%, and so forth, with 15-30% being more typical, even moretypically 20-25%). In various embodiments, the radiographic marker couldbe a spherical shape or a ring around the depot.

In some embodiments, the drug depot has pores that allow release of thedrug from the depot. The drug depot will allow fluid in the depot todisplace the drug. However, cell infiltration into the depot will beprevented by the size of the pores of the depot. In this way, in someembodiments, the depot will not function as a tissue scaffold and willnot allow tissue growth. Rather, the drug depot will solely be utilizedfor drug delivery. In some embodiments, the pores in the drug depot willbe less than 250 to 500 microns. This pore size will prevent cells frominfiltrating the drug depot and laying down scaffolding cells. Thus, inthis embodiment, drug will elute from the drug depot as fluid enters thedrug depot, but cells will be prevented from entering. In someembodiments, where there are little or no pores, the drug will elute outfrom the drug depot by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In otherembodiments, the drug depot may have pore sizes above 500 microns toallow influx of cells and drug release and the drug depot may function,in this embodiment, as a tissue scaffold.

In one exemplary embodiment, a drug depot for delivering a therapeuticagent to a target tissue site beneath the skin of a patient is provided,the drug depot comprising an effective amount of bupivacaine, whereinthe target tissue site comprises at least one muscle, ligament, tendon,cartilage, spinal disc, spinal foraminal space near the spinal nerveroot, facet or synovial joint, or spinal canal.

In various embodiments, the drug depot comprises a gel, which includes asubstance having a gelatin, jelly-like, or colloidal properties at roomtemperature. The gel, in various embodiments, may have the bupivacaineand optionally one or more additional therapeutic agents dispersedthroughout it or suspended within the gel. The dispersal of thetherapeutic agent may be even throughout the gel. Alternatively, theconcentration of the therapeutic agent may vary throughout it. As thebiodegradable material of the gel or drug depot degrades at the site,the therapeutic agent is released.

When the drug depot is a gel, in contrast to a sprayable gel thattypically employs a low viscosity polymer, a gel with a higher viscositymay be desirable for other applications, for example, a gel having aputty-like consistency may be more preferable for bone regenerationapplications. In various embodiments, when a polymer is employed in thegel, the polymeric composition includes about 10 wt. % to about 50 wt. %or about 15 wt. % to about 30 wt. % of the polymer.

In another exemplary embodiment, the gel is in viscous form is loadedwith one or more drug depots (e.g., microspheres loaded with atherapeutic agent), wherein the viscous gel is positioned into asynovial joint, disc space, a spinal canal, or a soft tissue surroundingthe spinal canal of a subject. The gel can also be used, in variousembodiments, to seal or repair tissue. In yet another exemplaryembodiment, the gel is injectable, and/or an adherent gel thatsolidifies upon contact with tissue. For example, the gel may beadministered as a liquid that gels in situ at the target tissue site. Invarious embodiments, the gel can comprise a two part system where aliquid is administered and a gelling agent is added subsequently tocause the liquid to gel or harden.

In various embodiments, the gel is a hardening gel, where after the gelis applied to the target site, it hardens and the drug can be releasedas the bodily fluid contacts the gel.

In various embodiments, the drug depot is loaded with bupivacaine andoptionally one or more additional therapeutic agents, and delivered tothe desired target tissue site (e.g., surgical wound site, inflammedtissue, degenerative tissue, etc.) and, in various embodiments, the drugdepot may be held in place by a suture, barb, staple, adhesive gel, etc.which prevents the drug depot from being removed from that site by thevenous systemic circulation or otherwise dispersed too widely, whichreduces the desired therapeutic effect. For example, after hours ordays, the drug depot may degrade, thereby allowing the drug depots(e.g., strips, ribbon-like strips, etc.) to begin releasing thetherapeutic agent. The strips may be formed from an insoluble or inertsubstance, but soluble or active once it comes into contact with thetarget tissue site. Likewise, the drug depot may comprise a substancethat dissolves or disperses within the tissue. As the drug depot beginsto dissolve within hours to days, the drug depots (e.g., strips) areexposed to body fluids and begin releasing their contents. The drugdepot can be formulated to optimize exposure time of the drug depot andrelease of the therapeutic agent from the drug depot.

In various embodiments, the drug depot (e.g., gel) is flowable and canbe injected, sprayed, instilled, and/or dispensed to, on or in thetarget tissue site. “Flowable” means that the gel formulation is easy tomanipulate and may be brushed, sprayed, dripped, painted, injected,shaped and/or molded at or near the target tissue site as it coagulates.“Flowable” includes formulations with a low viscosity or water-likeconsistency to those with a high viscosity, such as a paste-likematerial. In various embodiments, the flowability of the formulationallows it to conform to irregularities, crevices, cracks, and/or voidsin the tissue site. For example, in various embodiments, the gel may beused to fill one or more voids in an osteolytic lesion.

In various embodiments, the drug depot comprises poly(alpha-hydroxyacids), PLGA, D,L-lactide-glycolide-ε-caprolactone, PLA, PG,polyethylene glycol conjugates of poly(alpha-hydroxy acids),polyorthoesters, poly(lactic acid-co-lysine), poly(lactide-co-urethane),poly(ester-co-amide), polyaspirins, polyphosphazenes, polyanhydrides;polyketals, collagen, starch, pre-gelatinized starch, hyaluronic acid,chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs, suchas alpha tocopheryl acetate, d-alpha tocopheryl succinate, D,L-lactide,D-lactide, L-lactide, D,L-lactide-caprolactone,D,L-lactide-glycolide-caprolactone, dextrans, vinylpyrrolidone,polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBT copolymer (polyactive),methacrylates, poly(N-isopropylacrylamide), PEO-PPO-PEO (pluronics),PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG(poly(d,l-lactide-co-glycolide), PLA-PLGA, poloxamer 407, PEG-PLGA-PEGtriblock copolymers, SAIB (sucrose acetate isobutyrate) or combinationsthereof. These one or more components allow the therapeutic agent to bereleased from the drug depot in a controlled and/or sustained manner.For example, the drug depot containing the therapeutic agent and apolymer matrix can be injected at the target tissue site and the polymermatrix breaks down over time (e.g., hours, days) within the targettissue site releasing bupivacaine and optionally additional therapeuticagents. Thus, the administration of the drug depot can be localized andoccur over a period of time (e.g., at least one day to about 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29 and 30 days).

The terms “sustained release” or “sustain release” (also referred to asextended release or controlled release) are used herein to refer to oneor more therapeutic agent(s) that is introduced into the body of a humanor other mammal and continuously releases a stream of one or moretherapeutic agents over a predetermined time period and at a therapeuticlevel sufficient to achieve a desired therapeutic effect throughout thepredetermined time period. Reference to a continuous release stream isintended to encompass release that occurs as the result ofbiodegradation in vivo of drug depot, or a matrix or component thereof,or as the result of metabolic transformation or dissolution of thetherapeutic agent(s) or conjugates of therapeutic agent(s).

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or absorption of the drug.

The two types of formulations (sustain release and immediate release)may be used in conjunction. The sustained release and immediate releasemay be in or more of the same depots. In various embodiments, thesustained release and immediate release may be part of separate depots.For example, a bolus or immediate release formulation of bupivacaine maybe placed at or near the target site and a sustain release formulationmay also be placed at or near the same site. Thus, even after the bolusbecomes completely accessible, the sustain release formulation wouldcontinue to provide the active ingredient for the intended tissue.

In various embodiments, the drug depot is designed to cause an initialburst dose of therapeutic agent within the first 48 hours or 24 hoursafter implantation. “Initial burst” or “burst effect” or “bolus dose”refers to the release of therapeutic agent from the drug depot duringthe first 48 hours or 24 hours after the drug depot comes in contactwith an aqueous fluid (e.g., synovial fluid, cerebral spinal fluid,etc.). In some embodiments, the drug depot is designed to avoid thisinitial burst effect.

In various embodiments, the drug depot contains one or more differentrelease layer(s) that releases a bolus dose of bupivacaine orpharmaceutically acceptable salt thereof (e.g., 100 mg to 800 mg,400-800 mg, or 100 mg to 200 mg at a target site beneath the skin) andone or more sustain release layer(s) that releases an effective amountof bupivacaine or pharmaceutically acceptable salt thereof over a periodof 3 to 30 days, 3 to 10 days, or 7 to 10 days. In various embodiments,the one or more immediate release layer(s) comprise PLGA, which degradesfaster than the one or more sustain release layer(s), which comprisesPLA, which degrades at a slower rate than the PLGA.

In various embodiments, when the drug depot comprises a gel, the gel mayhave a pre-dosed viscosity in the range of about 1 to about 500centipoise (cps), 1 to about 200 cps, or 1 to about 100 cps. After thegel is administered to the target site, the viscosity of the gel willincrease.

In one embodiment, the gel may be an adherent gel, which comprises atherapeutic agent that is evenly distributed throughout the gel. The gelmay be of any suitable type, as previously indicated, and should besufficiently viscous so as to prevent the gel from migrating from thetargeted delivery site once deployed; the gel should, in effect, “stick”or adhere to the targeted tissue site. The gel may, for example,solidify upon contact with the targeted tissue or after deployment froma targeted delivery system. The targeted delivery system may be, forexample, a syringe, a catheter, needle or cannula or any other suitabledevice. The targeted delivery system may inject or spray the gel into oron the targeted tissue site. The therapeutic agent may be mixed into thegel prior to the gel being deployed at the targeted tissue site. Invarious embodiments, the gel may be part of a two-component deliverysystem and when the two components are mixed, a chemical process isactivated to form the gel and cause it to stick or adhere to the targettissue.

In various embodiments, for those gel formulations that contain apolymer, the polymer concentration may affect the rate at which the gelhardens (e.g., a gel with a higher concentration of polymer maycoagulate more quickly than gels having a lower concentration ofpolymer). In various embodiments, when the gel hardens, the resultingmatrix is solid but is also able to conform to the irregular surface ofthe tissue (e.g., recesses and/or projections in bone).

The percentage of polymer present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be preferred insome instances, for example, when applying the formulation via spray.

In various embodiments, the molecular weight of the gel can be varied bymany methods known in the art. The choice of method to vary molecularweight is typically determined by the composition of the gel (e.g.,polymer, versus non-polymer). For example, in various embodiments, whenthe gel comprises one or more polymers, the degree of polymerization canbe controlled by varying the amount of polymer initiators (e.g. benzoylperoxide), organic solvents or activator (e.g. DMPT), crosslinkingagents, polymerization agent, and/or reaction time.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel, which includes a high molecular weight polymer, tends tocoagulate or solidify more quickly than a polymeric composition, whichincludes a low-molecular weight polymer. Polymeric gel formulations,which include high molecular weight polymers, also tend to have a highersolution viscosity than a polymeric gel, which include a low-molecularweight polymer.

In various embodiments, the gel has an inherent viscosity (abbreviatedas “I.V.” and units are in deciliters/gram), which is a measure of thegel's molecular weight and degradation time (e.g., a gel with a highinherent viscosity has a higher molecular weight and longer degradationtime). Typically, a gel with a high molecular weight provides a strongermatrix and the matrix takes more time to degrade. In contrast, a gelwith a low molecular weight degrades more quickly and provides a softermatrix. In various embodiments, the gel has an inherent viscosity, fromabout 0.10 dL/g to about 1.2 dL/g or from about 0.10 dL/g to about 0.40dL/g. Other IV ranges include but are not limited to about 0.05 to about0.15 dL/g, about 0.10 to about 0.20 dL/g, about 0.15 to about 0.25 dL/g,about 0.20 to about 0.30 dL/g, about 0.25 to about 0.35 dL/g, about 0.30to about 0.35 dL/g, about 0.35 to about 0.45 dL/g, about 0.40 to about0.45 dL/g, about 0.45 to about 0.50 dL/g, about 0.50 to about 0.70 dL/g,about 0.60 to about 0.80 dL/g, about 0.70 to about 0.90 dL/g, and about0.80 to about 1.00 dL/g.

In various embodiments, the gel can have a viscosity of about 300 toabout 5,000 centipoise (cp). In other embodiments, the gel can have aviscosity of from about 5 to about 300 cps, from about 10 cps to about50 cps, from about 15 cps to about 75 cps at room temperature, whichallows it to be sprayed at or near the target site.

In various embodiments, the drug depot may comprise material to enhanceviscosity and control the release of the drug. Such material mayinclude, for example, hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethyl methylcellulose, carboxymethylcelluloseand salts thereof, Carbopol, poly(hydroxyethylmethacrylate),poly(methoxyethylmethacrylate), poly(methoxyethoxy-ethylmethacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, PEG 200, PEG 300, PEG 400, PEG500, PEG 550, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450,PEG 3350, PEG 4500, PEG 8000 or combinations thereof. For example, invarious embodiments, the drug depot comprises from about 25% to 75% byweight bupivacaine, about 15% to 75% by weightD,L-lactide-glycolide-caprolactone, and about 5% to 10% by weight of PEG300. The drug depot can also comprise from about 1% to 15% NMP.

The drug depot release profile can also be controlled, among otherthings, by controlling the particle size distribution of the componentsof the drug depot. In various embodiments, the particle sizedistribution of the components of the drug depot (e.g., bupivacaine,gel, etc.) may be in the range of from about 10 μM to 200 μM so that thedrug depot can easily be delivered to or at or near the target site byinjection, spraying, instilling, etc. In various embodiments, theparticle size may be 10 μM, 13 μM, 85 μM, 100 μM, 151 μM, 200 μM and allsubranges therebetween.

In various embodiments, the drug depot may comprise a hydrogel made ofhigh molecular weight biocompatible elastomeric polymers of synthetic ornatural origin. A desirable property for the hydrogel to have is theability to respond rapidly to mechanical stresses, particularly shearsand loads, in the human body.

Hydrogels obtained from natural sources are particularly appealing sincethey are more likely to be biodegradable and biocompatible for in vivoapplications. Suitable hydrogels include natural hydrogels, such as forexample, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides, or a combination thereof. Synthetichydrogels include, but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid andpoly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol(e.g., PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyether-urethane, or a combination thereof.

In various embodiments, rather than directly admixing the therapeuticagent into the gel, microspheres may be dispersed within the gel, themicrospheres being loaded with bupivacaine. In one embodiment, themicrospheres provide for a sustained release of the bupivacaine. In yetanother embodiment, the gel, which is biodegradable, prevents themicrospheres from releasing the bupivacaine; the microspheres thus donot release the bupivacaine until they have been released from the gel.For example, a gel may be deployed around a target tissue site (e.g., anerve root). Dispersed within the gel is a plurality of microspheresthat encapsulate the desired therapeutic agent. Certain of thesemicrospheres degrade once released from the gel, thus releasing thebupivacaine.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type, and hence disperse thebupivacaine. In some situations, this may be desirable; in others, itmay be more desirable to keep the bupivacaine tightly constrained to awell-defined target site. The present invention also contemplates theuse of adherent gels to so constrain dispersal of the therapeutic agent.These gels may be deployed, for example, in a disc space, in a spinalcanal, or in surrounding tissue.

Drug Delivery

It will be appreciated by those with skill in the art that the depot canbe administered to the target site using a “cannula” or “needle” thatcan be a part of a drug delivery device e.g., a syringe, a gun drugdelivery device, or any medical device suitable for the application of adrug to a targeted organ or anatomic region. The cannula or needle ofthe drug depot device is designed to cause minimal physical andpsychological trauma to the patient.

Cannulas or needles include tubes that may be made from materials, suchas for example, polyurethane, polyurea, polyether(amide), PEBA,thermoplastic elastomeric olefin, copolyester, and styrenicthermoplastic elastomer, steel, aluminum, stainless steel, titanium,metal alloys with high non-ferrous metal content and a low relativeproportion of iron, carbon fiber, glass fiber, plastics, ceramics orcombinations thereof. The cannula or needle may optionally include oneor more tapered regions. In various embodiments, the cannula or needlemay be beveled. The cannula or needle may also have a tip style vitalfor accurate treatment of the patient depending on the site forimplantation. Examples of tip styles include, for example, Trephine,Cournand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford,deflected tips, Hustead, Lancet, or Tuohey. In various embodiments, thecannula or needle may also be non-coring and have a sheath covering itto avoid unwanted needle sticks.

The dimensions of the hollow cannula or needle, among other things, willdepend on the site for implantation. For example, the width of theepidural space is only about 3-5 mm for the thoracic region and about5-7 mm for the lumbar region. Thus, the needle or cannula, in variousembodiments, can be designed for these specific areas. In variousembodiments, the cannula or needle may be inserted using atransforaminal approach in the spinal foramen space, for example, alongan inflammed nerve root and the drug depot implanted at this site fortreating the condition. Typically, the transforaminal approach involvesapproaching the intervertebral space through the intervertebralforamina.

Some examples of lengths of the cannula or needle may include, but arenot limited to, from about 50 to 150 mm in length, for example, about 65mm for epidural pediatric use, about 85 mm for a standard adult andabout 110 mm for an obese adult patient. The thickness of the cannula orneedle will also depend on the site of implantation. In variousembodiments, the thickness includes, but is not limited to, from about0.05 to about 1.655. The gauge of the cannula or needle may be thewidest or smallest diameter or a diameter in between for insertion intoa human or animal body. The widest diameter is typically about 14 gauge,while the smallest diameter is about 22 gauge. In various embodimentsthe gauge of the needle or cannula is about 18 to about 22 gauge.

In various embodiments, like the drug depot and/or gel, the cannula orneedle includes dose radiographic markers that indicate location at ornear the site beneath the skin, so that the user may accurately positionthe depot at or near the site using any of the numerous diagnosticimaging procedures. Such diagnostic imaging procedures include, forexample, X-ray imaging or fluoroscopy. Examples of such radiographicmarkers include, but are not limited to, barium, calcium, and/or metalbeads or particles.

In various embodiments, the needle or cannula may include a transparentor translucent portion that can be visualizable by ultrasound,fluoroscopy, x-ray, or other imaging techniques. In such embodiments,the transparent or translucent portion may include a radiopaque materialor ultrasound responsive topography that increases the contrast of theneedle or cannula relative to the absence of the material or topography.

The drug depot, and/or medical device to administer the drug may besterilizable. In various embodiments, one or more components of the drugdepot, and/or medical device to administer the drug are sterilized byradiation in a terminal sterilization step in the final packaging.Terminal sterilization of a product provides greater assurance ofsterility than from processes such as an aseptic process, which requireindividual product components to be sterilized separately and the finalpackage assembled in a sterile environment.

Typically, in various embodiments, gamma radiation is used in theterminal sterilization step, which involves utilizing ionizing energyfrom gamma rays that penetrates deeply in the device. Gamma rays arehighly effective in killing microorganisms, they leave no residues norhave sufficient energy to impart radioactivity to the device. Gamma rayscan be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device. E-beam radiationcomprises a form of ionizing energy, which is generally characterized bylow penetration and high-dose rates. E-beam irradiation is similar togamma processing in that it alters various chemical and molecular bondson contact, including the reproducing cells of microorganisms. Beamsproduced for e-beam sterilization are concentrated, highly-chargedstreams of electrons generated by the acceleration and conversion ofelectricity. E-beam sterilization may be used, for example, when thedrug depot is included in a gel.

Other methods may also be used to sterilize the depot and/or one or morecomponents of the device, including, but not limited to, gassterilization, such as, for example, with ethylene oxide or steamsterilization.

In various embodiments, a kit is provided that may include additionalparts along with the drug depot and/or medical device combined togetherto be used to implant the drug depot (e.g., ribbon-like strips). The kitmay include the drug depot device in a first compartment. The secondcompartment may include a canister holding the drug depot and any otherinstruments needed for the localized drug delivery. A third compartmentmay include gloves, drapes, wound dressings and other proceduralsupplies for maintaining sterility of the implanting process, as well asan instruction booklet. A fourth compartment may include additionalcannulas and/or needles. Each tool may be separately packaged in aplastic pouch that is radiation sterilized. A cover of the kit mayinclude illustrations of the implanting procedure and a clear plasticcover may be placed over the compartments to maintain sterility.

In various embodiments, a method for delivering bupivacaine into atarget tissue site of a patient is provided. The method comprisesinserting a cannula or needle at or near a target tissue site andimplanting the drug depot containing the bupivacaine at the target sitebeneath the skin of the patient. In various embodiments, to administerthe drug depot to the desired site, first the cannula or needle can beinserted through the skin and soft tissue down to the target tissue siteand the drug depot administered (e.g., injected, implanted, instilled,sprayed, etc.) at or near the target site. In those embodiments wherethe drug depot is separate from the gel, first the cannula or needle canbe inserted through the skin and soft tissue down to the site ofinjection and one or more base layer(s) of gel can be administered tothe target site. Following administration of the one or more baselayer(s), the drug depot can be implanted on or in the base layer(s) sothat the gel can hold the depot in place or reduce migration. Ifrequired, a subsequent layer or layers of gel can be applied on the drugdepot to surround the depot and further hold it in place. Alternatively,the drug depot may be implanted or injected first and then the gelplaced (e.g., brushed, dripped, injected, or painted, etc.) around thedrug depot to hold it in place. By using the gel, accurate and preciseimplantation of a drug depot can be accomplished with minimal physicaland psychological trauma to the patient. In various embodiments, thedrug depot can be sutured to the target site or alternatively the drugdepot can be implanted, without suturing. For example, in variousembodiments, the drug depot can be a strip-shaped or ribbon-shaped depotand placed at the target site, before, during or after surgery. Asanother example, the drug depot can be delivered in the form of a gelvia a syringe or other injectable delivery directly to the target site,before, during or after surgery.

In various embodiments, when the target tissue site comprises a spinalregion, a portion of fluid (e.g., spinal fluid, etc.) can be withdrawnfrom the target site through a cannula or needle first and then thedepot administered (e.g., placed, dripped, injected, or implanted,etc.). The target site will re-hydrate (e.g., replenishment of fluid)and this aqueous environment will cause the drug to be released from thedepot.

Treating or treatment of a disease or condition refers to executing aprotocol, which may include administering one or more drugs to a patient(human, other normal or otherwise), in an effort to alleviate signs orsymptoms of the disease. Alleviation can occur prior to signs orsymptoms of the disease or condition appearing, as well as after theirappearance. Thus, “treating” or “treatment” may include “preventing” or“prevention” of disease or undesirable condition. In addition,“treating” or “treatment” does not require complete alleviation of signsor symptoms, does not require a cure, and specifically includesprotocols that have only a marginal effect on the patient. “Reducingpain” includes a decrease in pain and does not require completealleviation of pain signs or symptoms, and does not require a cure. Invarious embodiments, reducing pain includes even a marginal decrease inpain. By way of example, the administration of one or more effectivedosages of bupivacaine may be used to prevent, treat or relieve thesymptoms of post-operative pain incidental to surgery.

“Localized” delivery includes delivery where one or more drugs aredeposited within, at or near a tissue. For example, localized deliveryincludes delivery to a nerve root of the nervous system or a region ofthe brain, or in close proximity (within about 10 cm, or preferablywithin about 5 cm, for example) thereto. “Targeted delivery system”provides delivery of one or more drugs depots (e.g., gels or depotdispersed in the gel, etc.) having a quantity of therapeutic agent thatcan be deposited at or near the target tissue site as needed fortreatment of pain and/or inflammation incidental to surgery.

FIG. 1 illustrates a number of common locations within a patient thatmay be sites at which surgery took place. It will be recognized that thelocations illustrated in FIG. 1 are merely exemplary of the manydifferent locations within a patient that may be at which surgery tookplace. For example, surgery may be required at a patient's knees 21,hips 22, fingers 23, thumbs 24, neck 25, and spine 26. Thus, during orfollowing these surgeries, the patient may be experiencingpost-operative pain and/or inflammation.

The term “pain” includes nociception and the sensation of pain, both ofwhich can be assessed objectively and subjectively, using pain scoresand other methods well-known in the art. In various embodiments, painmay include allodynia (e.g., increased response to a normallynon-noxious stimulus) or hyperalgesia (e.g., increased response to anormally noxious or unpleasant stimulus), which can in turn be thermalor mechanical (tactile) in nature. In some embodiments, pain ischaracterized by thermal sensitivity, mechanical sensitivity and/orresting pain. In other embodiments, pain comprises mechanically-inducedpain or resting pain. In still other embodiments, the pain comprisesresting pain. The pain can be primary or secondary pain, as iswell-known in the art. Exemplary types of pain reducible, preventable ortreatable by the methods and compositions disclosed herein include,without limitation, include post-operative pain, for example, from theback in the lumbar regions (lower back pain) or cervical region (neckpain), leg pain, radicular pain (experienced in the lower back and legfrom lumber surgery in the neck and arm from cervical surgery), orabdominal pain from abdominal surgery, and neuropathic pain of the arm,neck, back, lower back, leg, and related pain distributions resultingfrom disk or spine surgery. Neuropathic pain may include pain arisingfrom surgery to the nerve root, dorsal root ganglion, or peripheralnerve.

In various embodiments, the pain results from “post-surgical pain” or“post-operative pain” or “surgery-induced pain”, which are used hereininterchangeably, and refer to pain arising in the recovery period ofseconds, minutes, hours, days or weeks following a surgical procedure(e.g., hernia repair, orthopedic or spine surgery, etc.). Surgicalprocedures include any procedure that penetrates beneath the skin andcauses pain and/or inflammation to the patient. Surgical procedure alsoincludes arthroscopic surgery, an excision of a mass, spinal fusion,thoracic, cervical, or lumbar surgery, pelvic surgery or a combinationthereof.

The term “pain management medication” includes one or more therapeuticagents that are administered to reduce, prevent, alleviate or removepain entirely. These include anti-inflammatory agents, muscle relaxants,analgesics, anesthetics, narcotics, etc., or combinations thereof.

In various embodiments, the post-surgical pain or post-operative pain orsurgery-induced pain, is accompanied by inflammation. Inflammation canbe an acute response to trauma or surgery. When tissues are damaged,TNF-α attaches to cells to cause them to release other cytokines thatcause inflammation. The purpose of the inflammatory cascade is topromote healing of the damaged tissue, but once the tissue is healed theinflammatory process does not necessarily end. Left unchecked, this canlead to degradation of surrounding tissues and associated pain. Thus,pain can become a disease state in itself. That is, when this pathway isactivated, inflammation and pain ensue. Often a vicious and seeminglyendless cycle of insult, inflammation, and pain sets in.

One exemplary embodiment where the depot is suitable for use in painand/or inflammation management (e.g., post-operative pain and/orinflammation management) is illustrated in FIG. 2. Schematically shownin FIG. 2 is a dorsal view of the spine and sites where the drug depotmay be inserted using a syringe, cannula or needle beneath the skin 34to a spinal site 30 (e.g., spinal disc space, spinal canal, soft tissuesurrounding the spine, nerve root, etc.) and one or more drug depots 28and 32 are delivered to various sites along the spine. In this way, whenseveral drug depots are to be implanted, they are implanted in a mannerthat optimizes location, accurate spacing, and drug distribution.

Although the spinal site is shown, as described above, the drug depotcan be delivered to any site beneath the skin, including, but notlimited to, at least one muscle, ligament, tendon, cartilage, spinaldisc, spinal foraminal space, near the spinal nerve root, or spinalcanal. In various embodiments, the drug depot containing bupivacaine canbe administered to the patient intra-operatively, intravenously,intramuscularly, continuous or intermittent infusion, intraperitoneal,intrasternal, subcutaneously, intrathecally, intradiskally,peridiskally, epidurally, perispinally, intraarticular injection,parenterally, or via combinations thereof. In some embodiments, theinjection is intrathecal, which refers to an injection into the spinalcanal (intrathecal space surrounding the spinal cord). An injection mayalso be into a muscle or other tissue.

In some embodiments, it is preferable to co-administer bupivacaine withan antagonist to counteract undesirable effects. Exemplary antagonistsinclude but are not limited to phentolamine, yohimbine, tolazoline andpiperoxane. Additionally, compounds such as 5-fluorodeoxyuridine (FUDR)and 3,4 dehydroprolene may also be included. These compounds may preventor reduce glial and fibroblastic scar formation associated with sometypes of surgeries.

The bupivacaine-based formulations of the present application may beused as medicaments in the form of pharmaceutical preparations. Thepreparations may be formed in an administration with a suitablepharmaceutical carrier that may be solid or liquid and organic orinorganic, and placed in the appropriate form for parenteral or otheradministration as desired. As persons of ordinary skill are aware, knowncarriers include but are not limited to water, gelatine, lactose,starches, stearic acid, magnesium stearate, sicaryl alcohol, talc,vegetable oils, benzyl alcohols, gums, waxes, propylene glycol,polyalkylene glycols and other known carriers for medicaments.

Parenteral administration may additionally include, for example, aninfusion pump that administers a pharmaceutical composition (e.g.,anesthetic and anti-inflammatory combination) through a catheter nearthe spine or one or more inflamed joints, an implantable mini-pump thatcan be inserted at or near the target site, an implantable controlledrelease device or sustained release delivery system that can release acertain amount of the statin per hour or in intermittent bolus doses.One example of a suitable pump for use is the SynchroMed® (Medtronic,Minneapolis, Minn.) pump. This pump has three sealed chambers. Onecontains an electronic module and battery. The second contains aperistaltic pump and drug reservoir. The third contains an inert gas,which provides the pressure needed to force the pharmaceuticalcomposition into the peristaltic pump. To fill the pump, thepharmaceutical composition is injected through the reservoir fill portto the expandable reservoir. The inert gas creates pressure on thereservoir, and the pressure forces the pharmaceutical compositionthrough a filter and into the pump chamber. The pharmaceuticalcomposition is then pumped out of the device from the pump chamber andinto the catheter, which will direct it for deposit at the target site.The rate of delivery of pharmaceutical composition is controlled by amicroprocessor. This allows the pump to be used to deliver similar ordifferent amounts of pharmaceutical composition continuously, atspecific times, or at set intervals between deliveries.

In various embodiments, where the target tissue site comprises bloodvessels, a vasoconstrictor may be employed in the drug depot. When thevasoconstrictor is released, it lengthens the duration of the anestheticresponse and reduces the systemic uptake of the anesthetic agent. Theanesthetic may be, for example, bupivacaine, and the vasoconstrictor maybe, for example, epinephrine or phenylephrine.

The term “patient” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc.

Method of Making Bupivacaine Depots

In various embodiments, the drug depot comprising the bupivacaine can bemade by combining a biocompatible polymer and a therapeuticallyeffective amount of bupivacaine or pharmaceutically acceptable saltthereof and forming the implantable drug depot from the combination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s), andoptional materials, including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example,biocompatible polymer and/or therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined and placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: bupivacaine and othertherapeutic agent(s) and other optional additives such as radiographicagent(s), etc. in dissolved or dispersed form. This results in apolymeric matrix region containing these species after solvent removal.In other embodiments, a solution containing solvent with dissolved ordispersed therapeutic agent is applied to a pre-existing polymericregion, which can be formed using a variety of techniques includingsolution processing and thermoplastic processing techniques, whereuponthe therapeutic agent is imbibed into the polymeric region.

Thermoplastic processing techniques for forming the depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: bupivacaine,optional additional therapeutic agent(s), radiographic agent(s), and soforth. The resulting mixture is then shaped into an implantable drugdepot. The mixing and shaping operations may be performed using any ofthe conventional devices known in the art for such purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, bupivacaine may undergo substantial degradationunder ordinary thermoplastic processing conditions. Hence, processing ispreferably performed under modified conditions, which prevent thesubstantial degradation of the therapeutic agent(s). Although it isunderstood that some degradation may be unavoidable during thermoplasticprocessing, degradation is generally limited to 10% or less. Among theprocessing conditions that may be controlled during processing to avoidsubstantial degradation of the therapeutic agent(s) are temperature,applied shear rate, applied shear stress, residence time of the mixturecontaining the therapeutic agent, and the technique by which thepolymeric material and the therapeutic agent(s) are mixed.

Mixing or compounding the biocompatible polymer with therapeuticagent(s) and any additional additives to form a substantially homogenousmixture thereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in various embodiments, a biocompatible polymer ispre-compounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the therapeutic agent, if it were present.This pre-compounded material is then mixed with therapeutic agent underconditions of lower temperature and mechanical shear, and the resultingmixture is shaped into the bupivacaine containing drug depot.Conversely, in another embodiment, the biocompatible polymer can bepre-compounded with the therapeutic agent under conditions of reducedtemperature and mechanical shear. This pre-compounded material is thenmixed with, for example, a radio-opacifying agent, also under conditionsof reduced temperature and mechanical shear, and the resulting mixtureis shaped into the drug depot.

The conditions used to achieve a mixture of the biocompatible polymerand therapeutic agent and other additives will depend on a number offactors including, for example, the specific biocompatible polymer(s)and additive(s) used, as well as the type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depotis formed comprising PLGA or PLA polymer, a radio-opacifying agent(e.g., bismuth subcarbonate), and a therapeutic agent prone todegradation by heat and/or mechanical shear, in various embodiments, thePGLA or PLA can be premixed with the radio-opacifying agent attemperatures of about, for example, 150° C. to 170° C. The therapeuticagent is then combined with the premixed composition and subjected tofurther thermoplastic processing at conditions of temperature andmechanical shear that are substantially lower than is typical for PGLAor PLA compositions. For example, where extruders are used, barreltemperature, volumetric output are typically controlled to limit theshear and therefore to prevent substantial degradation of thetherapeutic agent(s). For instance, the therapeutic agent and premixedcomposition can be mixed/compounded using a twin screw extruder atsubstantially lower temperatures (e.g., 100-105° C.), and usingsubstantially reduced volumetric output (e.g., less than 30% of fullcapacity, which generally corresponds to a volumetric output of lessthan 200 cc/min). It is noted that this processing temperature is wellbelow the melting points of bupivacaine, because processing at or abovethese temperatures will result in substantial therapeutic agentdegradation. It is further noted that in certain embodiments, theprocessing temperature will be below the melting point of all bioactivecompounds within the composition, including the therapeutic agent. Aftercompounding, the resulting depot is shaped into the desired form, alsounder conditions of reduced temperature and shear.

In other embodiments, biodegradable polymer(s) and one or moretherapeutic agents are premixed using non-thermoplastic techniques. Forexample, the biocompatible polymer can be dissolved in a solvent systemcontaining one or more solvent species. Any desired agents (for example,a radio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing drug depot(the pre-existing drug depot can be formed using a variety of techniquesincluding solution and thermoplastic processing techniques, and it cancomprise a variety of additives including a radio-opacifying agentand/or viscosity enhancing agent), whereupon the therapeutic agent isimbibed on or in the drug depot. As above, the resulting solid materialcan then be granulated for further processing, if desired.

Typically, an extrusion process may be used to form the drug depotcomprising a biocompatible polymer(s), therapeutic agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric matrix layers or regions that have permeability tofluids to allow immediate and/or sustained drug release). Multi-regiondepots can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., ribbon, pellet, strip, etc.) is cooled. Examples ofcooling processes include air cooling and/or immersion in a coolingbath. In some embodiments, a water bath is used to cool the extrudeddepot. However, where the therapeutic agent is water-soluble, theimmersion time should be held to a minimum to avoid unnecessary loss oftherapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this is release profile is not desired.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot to thedesired shape. In various embodiments, bupivacaine is used and mixed orsprayed with PLGA, poly(D,L-lactide-caprolactone) polymer, and/orpoly(D,L-lactide-glycolide-caprolactone) polymer and the resulting depotmay be formed by extrusion and dried.

In some exemplary formulations, there may be 55-65% bupivacaine, 25-35%PLGA and 5-15% mPEG. Some of these formulations will release between 10and 30% of the active ingredient on day 1 and all or substantially allof the active ingredient by day 10. Some of these formulations willrelease between 15 and 25% of the active ingredient on day 1 and all orsubstantially all of the product by day 10.

In still other exemplary formulations, there may be 55-65% bupivacaine,25-35% DL-G-CL, 6% PEG 300 and 13% NMP. Some of these formulations willrelease between 10 and 30% of the active ingredient on day 1 and all orsubstantially all of the active ingredient by day 10. Some of theseformulations will release between 10 and 15% of the active ingredient onday 1 and all or substantially all of the product by day 10.

In another exemplary embodiment, an implantable drug depot useful forreducing, preventing or treating post-operative pain in a patient inneed of such treatment is provided. The implantable drug depot comprisesa therapeutically effective amount of bupivacaine or pharmaceuticallyacceptable salt thereof. The depot is implantable at a site beneath theskin to reduce, prevent or treat post-operative pain wherein the drugdepot comprises (i) one or more immediate release layer(s) that iscapable of releasing about 5% to about 50% of the bupivacaine orpharmaceutically acceptable salt thereof relative to a total amount ofthe bupivacaine or pharmaceutically acceptable salt thereof loaded inthe drug depot over a first period of up to 48 hours, a first period ofup to 24 hours, or a first period of about 24 to 48 hours and (ii) oneor more sustain release layer(s) that is capable of releasing about 50%to about 95% of the bupivacaine or pharmaceutically acceptable saltthereof relative to a total amount of the bupivacaine orpharmaceutically acceptable salt thereof loaded in the drug depot over asubsequent period of up to 4 to 30 or 4 to 10 days. The one or moreimmediate release layer(s) comprise one or more ofpoly(lactide-co-glycolide), polylactide, polyglycolide, polyorthoester,D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide,poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof, and the one or more sustain release layer(s)comprise one or more of poly(lactide-co-glycolide), polylactide,polyglycolide, polyorthoester, D-lactide, D,L-lactide,poly(D,L-lactide), L-lactide, poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof.

In yet another exemplary embodiment, an implantable drug depot isprovided. The implantable drug depot comprises: (i) a therapeuticallyeffective amount of bupivacaine or pharmaceutically acceptable saltthereof; (ii) one or more immediate release layer(s) that is capable ofreleasing a bolus dose of bupivacaine or pharmaceutically acceptablesalt thereof at a site beneath the skin; and (iii) one or more sustainrelease layer(s) that is capable of releasing an effective amount ofbupivacaine or pharmaceutically acceptable salt thereof over a period of4 to 30 days, 4 to 10 days, or 5 to 7 days. The one or more immediaterelease layer(s) comprise one or more of poly(lactide-co-glycolide),polylactide, polyglycolide, polyorthoester, D-lactide, D,L-lactide,poly(D,L-lactide), L-lactide, poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof, and the one or more sustain release layer(s)comprise one or more of poly(lactide-co-glycolide), polylactide,polyglycolide, polyorthoester, D-lactide, D,L-lactide,poly(D,L-lactide), L-lactide, poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof. The drug depot is capable of releasing about 40% toabout 70% of the bupivacaine or pharmaceutically acceptable salt thereofrelative to a total amount of bupivacaine loaded in the drug depot overthe sustained release period.

Having now generally described the invention, the same may be morereadily understood through the following reference to the followingexamples, which are provided by way of illustration and are not intendedto limit the present invention unless specified.

EXAMPLES Example 1

Implants comprising bupivacaine were prepared according to the followingprocedures:

Materials: Poly(D,L-lactide-co-caprolactone) having a 25:75 lactide tocaprolactone molar ratio (25:75 DL-CL), an intrinsic viscosity of 0.8dL/g and a molecular weight of 95 kDa was purchased from LakeshoreBiomaterials (Birmingham, Ala.).Poly(D,L-lactide-co-glycolide-co-caprolactone) having a 30:20:50 lactideto glycolide to caprolactone molar ratio (30:20:50 DL-G-CL), anintrinsic viscosity of 0.05 dL/g to 0.15 dL/g and a molecular weight of10 kDa was purchased from Lakeshore Biomaterials (Birmingham, Ala.).Bupivacaine Base was purchased from Orgamol (Switzerland). Polyethyleneglycol (PEG) having an average molecular weight of 300-400 g/mol waspurchased from Spectrum Chemicals, n-methylpyrrolidone (NMP) having anaverage molecular weight of 99 g/mol was purchased from Fisher, andacetone was also purchased from Sigma-Aldrich.

Methods:

Preparation of Bupivacaine base/25:75 DL-CL strip implant: The 25:75DL-CL polymer was added to a glass vial and heated to either 100° C.(below drug melt temp) or 110° C. (above drug melt temp). Bupivacainebase was added to the melted polymer and mixed with a spatula untilvisually homogeneous. The resulting blend was removed from the glassvial and pressed into a thin film (0.4-0.6 mm thickness) using a CarverPress. The Carver Press was operated at 45° C. and 6000-8000 psipressure. The thin film was cut to form a strip of the desireddimensions with a sharp blade. The dimensions of the implant were 9 mmin length, 0.4 to 1 mm in thickness and 1.5 to 3 mm in width. Thedimensions of the implant were chosen for in vivo testing in the Brennanrat post-operative pain model.

Preparation of Bupivacaine base/30:20:50 DL-G-CL injectable paste/gelformulation: The polymer (318 mg), PEG 300 (92 mg) and NMP (199 mg) wereadded to a glass vial and heated to 93° C. for approximately 10 minutes.Bupivacaine (911 mg) was added to the mixture and maintained at 93° C.for 20 minutes while being stirred/vortexed to get the drug to dissolve.Vail was removed from the heat and the mixture was stirred as it cooledto room temperature. The formulation was collected from the vial andadded to a 1 mL syringe. The mixture was easily expelled from thesyringe (no needle attached) when heated to 40° C.

In Vitro Drug Elution Testing of Bupivacaine base/25:75 DL-CL ribbonimplant and Bupivacaine base/30:20:50 DL-G-CL injectable gelformulation: The purpose of this procedure was to measure the release ofbupivacaine from a polymer implant and a gel formulation into areceiving fluid PBS buffer, pH 7.4. The in vitro release procedureconsisted of placing a known mass of implant or gel into an apparatuscontaining the receiving fluid. The in vitro release apparatus consistedof a 60 ml glass bottle. A receiving fluid in the amount of 30 ml wasadded to each sample bottle. During the release study, the apparatus wasplaced in an incubator maintained at 37±2° C. At predeterminedintervals, samples of the receiving fluid were removed and analyzed forbupivacaine concentration by HPLC.

Elution profile and in vivo data: Implants of these formulations ofbupivacaine were tested in Brennan rats to determine their in vitroelution and in vivo performance. FIGS. 3 and 4 show the averagecumulative release profiles of these bupivacaine formulations. Also, theelution profiles and in vivo data for these formulations are summarizedbelow in Table 1:

TABLE 1 Active Wt. % In vitro Formulation of Handling elution NumberPolymer Bupivacaine Excipient Property profile In vivo data bupivacaine1 2575 DL-CL 63% None Malleable Day 1 burst Some efficacy 8E(bupivacaine release of in Brennan rat base) 22%. 97% eluted by day 10.bupivacaine 2 30:20:50 60% 6% PEP Injectable Day 1 release Could notDL-G-CL (bupivacaine 300, Paste of 12%, 75% demonstrate 1E base) 13% NMPof the drug eluted by day 10

DL-CL is an abbreviation for poly(DL-lactide-co-caprolactone) polymer.

FIGS. 5 and 6 show the efficacy data for in vivo testing for bupivacaine1 and 2 formulations. In FIGS. 5 and 6, “n” represents the number ofanimals evaluated. In FIG. 6, for each of the 4 groups (surgery, controlpaste, bupivacaine paste and bupivacaine polymer), eight time points areprovided. The time points are from left to right baseline, day 1post-surgery, day 2 post-surgery, day 3 post-surgery, day 4post-surgery, day 7 post-surgery, day 8 post-surgery and day 10post-surgery.

For the bupivacaine 1 formulation, there was a concern that theco-polymer could take up to 6-8 months to fully degrade. No excipientwas needed because the bupivacaine was melted before it was mixed withthe polymer. The malleability was of sufficient flexibility to permitextrusion to a strip or ribbon dosage form. As a preliminary evaluation,the efficacy of this formulation was tested in the Brennan rat model ofpost-incisional pain. Mechanical allodynia was used as the behavioralendpoint to assess the presence/absence of pain in the animal modelfollowing treatment with these formulations. The Brennan rat incisionwas made on the plantar aspect of the rat paw. The depth and length ofthe incision was a limiting factor in this model as the implant size wasa bit bigger for the incision and became bulky in the rats' pawfollowing implantation. This in turn affected wound healing. Someimplants were lost from the incised paw at different timepointsfollowing administration. Due to this issue, some animals were excludedfrom the study due to the loss of implants and a complete evaluation ofthe efficacy of these formulations with only the few rats remaining inthe study was not possible. However, of the few rats that proceededthrough the study, some efficacy in reversing mechanical allodyniafollowing the administration of the bupivacaine 1 formulation was noted.

For the bupivacaine 2 formulation, the degradation of the polymer wasless than one month. The effect of the bupivacaine 2 formulation was notable to be demonstrated due to the fact that the handling property ofthe injectable formulation was changed at the time for administration.The formulation stability was affected during shipping. In the in vivotests, although only some efficacy was seen (such as that with thebupivacaine 1 formulation), it is understood that in the Brennan ratmodel, efficacy is affected by the absence of an effective drug dose inthe formulation strip dimension cut to fit the incision in the model.

Example 2

A number of implants comprising bupivacaine were prepared according tothe following procedures:

Materials: Poly(D,L-lactide-co-glycolide) having a 50:50 lactide toglycolide molar ratio (PLGA 50501A), an intrinsic viscosity of 0.12 andacid end capped polymer chain ends was purchased from LakeshoreBiomaterials (Birmingham, Ala.). Bupivacaine Base was purchased fromOrgamol (Switzerland). Bupivacaine HCl was purchased from SpectrumChemicals (Gardena, Calif.). Methoxy polyethylene glycol (mPEG) havingan average molecular weight of 550 was purchased from Sigma-Aldrich.Methanol and acetone was also purchased from Sigma-Aldrich.

Methods:

Preparation of Spray Dried Bupivacaine base/PLGA50501A: Bupivacaine baseand PLGA50501A were both dissolved in acetone to yield a 10% (w/w)solution. A mixture of 65.2% bupivacaine base solution and 34.8%PLGA50501A solution was spray dried in the Buchi Spray Dryer. Theprocessing parameters were set as follows: inlet temp. (70° C.),aspirator (80%), nitrogen inlet (50 mm), spray flow rate (80 mL/hr) andultrasonic generator (0.8 watts). The spray dried powder was collectedand dried for an additional 24 hours at 30° C. and 15 mmHg vacuum.

Preparation of Spray Dried Bupivacaine HCl: Bupivacaine HCl wasdissolved in methanol to yield a 10% (w/w) solution and the solution wasspray dried in the Buchi Spray Dryer. The processing parameters were setas follows: inlet temp. (70° C.), aspirator (80%), nitrogen inlet (50mm), spray flow rate (80 mL/hr) and ultrasonic generator (0.8 watts).The spray dried powder was collected and dried for additional 24 hoursat 70° C. and 15 mm Hg vacuum.

Preparation of Melt Extruded Rods: Three formulations were prepared formelt extrusion. All three formulations contained PLGA50501A ground intopowder using a Retsch (Retsch GmbH, Germany) rotor mill with an 80micrometer sieve filter. The first such formulation contained 30% (w/w)ground PLGA50501A, 60% (w/w) spray dried bupivacaine HCl, and 10% (w/w)mPEG (60% bupivacaine HCl). The second formulation contained 90% (w/w)spray dried bupivacaine base/PLGA50501A and 10% (w/w) mPEG (60%bupivacaine base). The last formulation contained 90% (w/w) groundPLGA50501A and 10% (w/w) mPEG (vehicle polymer). The last formulationwas not tested.

The first two formulations were dry mixed with a spatula prior to beingfeed into a Haake Mini-Lab twin screw extruder (Thermo FischerScientific, Waltham, Mass.). The extruder settings were as follows: 105°C. and 30 RPM for the 60% bupivacaine HCl formulation, and 85° C. and 30RPM for the 60% bupivacaine base formulation. The first two formulationswere extruded out of a 1.5 mm diameter die.

Strip Preparation: Extruded formulations were pressed into sheets of adesired thickness using a Carver Laboratory Heat Press (Carver, Inc.,Wabash, Ind.) set at 50° C. The sheets were cut by razor blades to formstrips (or ribbons) or implants of the desired dimensions. Thedimensions of each implant were as follows (length by width by height orL×W×H): for the 60% bupivacaine base formulation, the implants were 9mm×3 m×1 mm and for the 60% bupivacaine HCl formulation, the implantswere 9 mm×3 mm×1 mm.

In Vitro Drug Elution Testing: Each strip or implant was tested intriplicate and placed in 20 mL scintillation vials for drug elutiontesting. The 60% bupivacaine HCl and 60% bupivacaine base strips (orribbons) were incubated in 10 mL of phosphate buffer with 0.5% (w/w)sodium dodecyl sulfate pH 7.4 at 37° C. under mild agitation. Atpre-selected times, the buffer was removed for analysis and replacedwith fresh buffer medium. The drug content was quantified at 260 nm forbupivacaine by Molecular Devices SpectraMax M2 (Sunnyvale, Calif.) platereader.

Elution profile and in vivo data: The implants of bupivacaine weretested in Brennan rats to determine their in vitro elution and in vivoperformance. FIGS. 7 and 8 show the average release rate of abupivacaine 3 implant (labeled as Bupivacaine HCl in the figures) and abupivacaine 4 implant (labeled as Bupivacaine Base in the figures) fromTable 2 in micrograms and percentages. FIG. 9 shows the thermal pawwithdrawal threshold in grams per days post-surgery for bupivacaine 3and 4 implants. The results are also summarized below in Table 2:

TABLE 2 Active wt. % In vitro Implant Polymer of Excipient Handlingelution Number (wt. %) Bupivacaine (wt. %) Property profile In vivo databupivacaine 3 30% PLGA 60% 10% mPEG Sticky, Day 1 release No statistical50501 A (bupivacaine malleable of 47%; by day reduction in HCl) 7, 100%hyperalgesia released bupivacaine 4 30% PLGA 60% 10% mPEG Sticky, Day 1release Statistically 50501 A (bupivacaine malleable of 20%; by daysignificant base) 9, 70% released reduction in mechanical hyperalgesiaon Day 2 bupivacaine 5 PLA-C12 gel 30% None Injectable Day 1 burst Nottested (bupivacaine release of 30%; base) by day 10, 70% of the drugeluted

For the bupivacaine 3 and 4 implants, the polymer degraded in less thanone month. The handling property was of a nature to enable a malleableand formable formulation product that could be extruded to a strip-like(ribbon) dosage form. As a preliminary evaluation, the efficacy of theseimplant formulations was tested in the Brennan rat model ofpost-incisional pain. Mechanical hyperalgesia was used as the behavioralendpoint to assess the presence/absence of pain in the animal modelfollowing treatment with these drug formulations. The Brennan ratincision was made on the plantar aspect of the rat paw. The depth andlength of the incision was a limiting factor in this model as an implantwas a little bigger than the incision and it became bulky in the ratspaw following implantation. This in turn affected wound healing. Someimplants were lost from the incised paw at different timepointsfollowing administration. Due to this issue, some animals were excludedfrom the study due to the loss of implants and a complete evaluation ofthe efficacy of these implants with the few rats remaining in the studywas not able to be conducted. However, of the few rats that proceededthrough the study, a statistically significant reduction in mechanicalhyperalgesia on day 2 post-surgery, following the administration of abupivacaine 4 implant, was noted whereas there was no statistical effectwith the administration of a bupivacaine 3 implant.

For the bupivacaine 5 implant, the degradation of the polymer took atleast a couple of months.

Example 3

A number of implants comprising bupivacaine base were prepared and theircumulative in vitro release profiles were measured.

Materials: Poly(D,L-lactide-co-caprolactone) having a 25:75 lactide tocaprolactone molar ratio (25:75 DL-CL), an intrinsic viscosity of 0.8dL/g and a molecular weight of 95 kDa was purchased from LakeshoreBiomaterials (Birmingham, Ala.).Poly(D,L-lactide-co-glycolide-co-caprolactone) having a 30:20:50 lactideto glycolide to caprolactone molar ratio (30:20:50 DL-G-CL), anintrinsic viscosity of 0.05 dL/g to 0.15 dL/g and a molecular weight of10 kDa was purchased from Lakeshore Biomaterials (Birmingham, Ala.).Bupivacaine base was purchased from Orgamol (Switzerland). The PEGpolymers having average molecular weights of 300, 1,500 and 8,000 werepurchased from Spectrum Chemicals, n-methylpyrroolidone (NMP) having anaverage molecular weight of 99 g/mol was purchased from Fisher, andacetone was also purchased from Sigma-Aldrich. Labrosol consisting ofPEG-8 caprylic/capric glycerides was purchased from Gattefosse, USA(Paramus, N.J.). Trehalose having an average molecular weight of 324g/mol was purchased from Sigma-Aldrich (St. Louis, Mo.).

Methods:

Preparation of Bupivacaine base/DL-CL strip implants: The 10:90, 25:75or 65:35 DL-CL polymer were each added to glass vials and heated toeither 100° C. (below drug melt temp) or 110° C. (above drug melt temp).Bupivacaine base was added to the melted polymers and mixed with aspatula until visually homogeneous. The resulting blend was removed fromthe glass vial and pressed into a thin film (0.4-0.6 mm thickness) usinga Carver Press. The Carver Press was operated at 45° C. and 6000-8000psi pressure. The thin film was cut to form strips (ribbons) of thedesired dimensions with a sharp blade. The dimensions of the implantswere 9 mm in length, 1.5 to 3 mm in width and 0.5 to 1 mm in thickness.

In Vitro Drug Elution Testing of Bupivacaine base/25:75 DL-CL ribbonimplants: The purpose of this procedure was to measure the release ofbupivacaine from a polymer implant formulation into a receiving fluidPBS buffer, pH 7.4. The in vitro release procedure consisted of placinga known mass of implant or gel into an apparatus containing thereceiving fluid. The in vitro release apparatus consisted of a 60 mlglass bottle. A receiving fluid in the amount of 30 ml was added to eachsample bottle. During the release study, the apparatus was placed in anincubator maintained at 37±2° C. At predetermined intervals, samples ofthe receiving fluid were removed and analyzed for bupivacaineconcentrations by HPLC. The drug loadings for these implants aresummarized in Table 3 below. In addition, Table 3 provides a descriptionfor each of these bupivacaine implants.

TABLE 3 Molar Batch Ratio of Drug Load Number Polymer Polymers Excipient(wt. %) Description/Shape 00180-25 DL-CL 10:90 None 62.16 extruded,ribbon shaped 00180-26 5050 4C PEG — None 71.34 extruded, ribbon shaped1500 00180-27 5050 2C PEG — None 58.96 extruded, ribbon shaped 150000180-28 DL-CL 8E 25:75 None 53.83 maleable, formable product 00180-36DL-CL 8E 25:75 None 70.88 maleable, formable product 00180-38 DL-CL 8E25:75 100 mg NMP 57.5 maleable, formable product 00180-39 DL-CL 8E 25:75None 61.7 maleable, formable product 00180-40 DL-CL 8E 25:75 None 60.6maleable, formable product 00180-53 DL-CL 4A 65:35 None 70 very hard,not very formable product 00180-54 DL-CL 5A 25:75 None 70 brittle,crumbly, not formable product 00180-55 DL-CL 5A 25:75 118 mg NMP 65.92maleable, formable product- 00180-56 DL-CL 4A 65:35 118 mg NMP 66.19investigation 00180-57 DL-CL 5A 25:75 20.5 mg 60.11 of lower MW polymerswith acid NMP end 00180-58 DL-CL 4A 65:35 45.6 mg 58.37 group chemistryNMP 00180-79-01 DL-CL 8E 25:75 2% PEG 62.69 somewhat tacky, easilyformable 1500 initially, after handling for a few minutes, the materialbecomes crumbly 00180-79-02 DL-CL 8E 25:75 2% PEG 61.9 somewhat tacky,easily formable, 8000 holds together much better than PEG1500formulation (180-79-01), does not crumble after prolonged handling00180-80-01 DL-CL 8E 25:75 2% 61.57 easy to handle, smooth texture,trehalose, formable 4% NMP 00180-80-03 DL-CL 8E 25:75 2% CMC, 4% 61.03tacky, easy to handle, formable NMP 00180-80-04 DL-CL 8E 25:75 4%labrosol 58.91 tacky, easy to handle, formable 00180-80-05 DL-CL 8E25:75 5% 5050 2C 60.49 flaky and crumbly, did not hold PEG 1500 togetherwell 00180-112 DL-CL 8E 25:75 None 62.03 maleable, formable product

Example 4

Several Bupivacaine Gel Formulations were Prepared.

Preparation of PLA Gel: Depolymerization of Polylactic Acid withDodecanol

Polylactic acid (intrinsic viscosity of 5.71 and weight of 15.0 grams),4-dimethylaminopyridine (weight of 9.16 grams), and dodecanol (weight of5.59 grams) were added into a 100 mL round bottom flask, charged, cappedwith a rubber septum and placed in an oil bath at 140° C. The materialswere heated at that temperature for 30 minutes after everything wasmelted and was stirred freely with a magnetic stir bar. After cooling,15 mL of tetrahydrofuran was added into the flask to dissolve thematerials and precipitated by adding heptane. After decanting off thesolvents, the material was dissolved in chloroform (30 mL) and washedwith hydrochloride (1 molar, 20 mL, three times) and brined once. Thesolution was dried over anhydrous sodium sulfate. Yellow oil wasobtained after solvent removal by rota-evaporation. (Mn about 800 g/molby end group analysis by H-NMR)

Method of Preparation of Bupivacaine Gel Formulations: The formulationswere prepared to contain 70% (w/w) PLA gel and 30% (w/w) spray driedbupivacaine. For each formulation, the two components were added to a 2cc transfer cup and mixed in a Flacktek, Inc. Speedmixer DAC 150 FVZ for2 minutes. The mixed formulations were each then back loaded into a 1 mLBD syringe with a 18G 1.5 inch blunt tip needle.

In Vitro Drug Elution Testing: 100 uL of each of the gel formulationswas injected in a 20 mL scintillation vial for drug elution testing. Theformulations were each tested in triplicate and incubated in 10 mL ofphosphate buffer with 0.5% (w/w) sodium dodecyl sulfate pH 7.4 at 37° C.under mild agitation. At pre-selected times, the buffer was removed foranalysis and replaced with fresh buffer medium. The drug content wasquantified for bupivacaine by a Molecular Devices SpectraMax M2(Sunnyvale, Calif.) plate reader. The resulting formulations included30% bupivacaine. FIGS. 10-12 show the average in vitro cumulativepercentage release of bupivacaine per day for the formulations which arelisted below in Table 4.

TABLE 4 Formulation ID Drug Load (%) 13335-80-1 30 13335-80-2 3013335-80-3 30 13335-80-4 30 13335-80-5 30 13335-80-6 30 13335-80-7 3013335-88-1 30 13335-88-2 30 13335-88-3 30 13335-88-4 30 13335-88-5 3013699-13-1 30

Example 5

A number of implants comprising bupivacaine were prepared according tothe following procedures:

Materials: Poly(D,L-lactide-co-glycolide) having a 50:50 lactide toglycolide molar ratio (DLG 50501A), an intrinsic viscosity of 0.12 andacid end capped polymer chain ends was purchased from LakeshoreBiomaterials (Birmingham, Ala.). Bupivacaine base was purchased fromOrgamol (Switzerland). Methoxy polyethylene glycol (mPEG) having anaverage molecular weight of 550 was purchased from Sigma-Aldrich.Methanol and acetone was also purchased from Sigma-Aldrich.

Methods:

Preparation of Spray Dried Bupivacaine base/DLG 50501A: Bupivacaine baseand DLG50501A were both dissolved in acetone to yield a 10% (w/w)solution. A mixture of 65.2% bupivacaine base solution and 34.8% DLG50501A solution was spray dried in the Buchi Spray Dryer. The processingparameters were set as follows: inlet temp. (70° C.), aspirator (80%),nitrogen inlet (50 mm), spray flow rate (80 mL/hr) and ultrasonicgenerator (0.8 watts). The spray dried powder was collected and driedfor an additional 24 hours at 30° C. and 15 mm Hg vacuum.

Preparation of Melt Extruded Rods: Several formulations were preparedfor melt extrusion. All formulations contained DLG 50501A ground intopowder using a Retsch (Retsch GmbH, Germany) rotor mill with an 80micrometer sieve filter. All formulations contained 60% (w/w) spraydried bupivacaine base/PLGA50501A.

The formulations were each dry mixed with a spatula prior to being fedinto a Haake Mini-Lab twin screw extruder (Thermo Fischer Scientific,Waltham, Mass.). The extruder settings were as follows: 105° C. and 30RPM for the 60% bupivacaine HCl formulation, and 85° C. and 30 RPM forthe 60% bupivacaine base formulation. The formulations were extruded outof a 1.5 mm diameter die.

Strip Preparation: Extruded formulations were pressed into sheets of adesired thickness using a Carver Laboratory Heat Press (Carver, Inc.,Wabash, Ind.) set at 50° C. The sheets were cut by razor blades to formstrips of the desired dimensions. The dimensions of each of the implantsor strips were 9 mm in length by 3 mm in width by 1 mm in height.

In Vitro Drug Elution Testing: Each strip or implant was tested intriplicate and placed in 20 mL scintillation vials for drug elutiontesting. The 60% bupivacaine base strips (or ribbons) were incubated in10 mL of phosphate buffer with 0.5% (w/w) sodium dodecyl sulfate pH 7.4at 37° C. under mild agitation. At pre-selected times, the buffer wasremoved for analysis and replaced with fresh buffer medium. The drugcontent was quantified at 260 nm for bupivacaine by Molecular DevicesSpectraMax M2 (Sunnyvale, Calif.) plate reader. FIGS. 13 and 14 show theaverage in vitro cumulative percentage release of bupivacaine per dayfor the implants which are listed below in Table 5.

TABLE 5 Ribbon Size Drug Load (mm) ID Number Polymer (%) Excipient (L ×W × H) 13335-76-1 5050 DLG 1A 60 5% mPEG 9 × 3 × 1 13335-76-2 5050 DLG2A 60 5% mPEG 9 × 3 × 1 13335-76-3 5050 DLG 1A 60 7% mPEG 9 × 3 × 113335-83-1 5050 DLG 1A 60 8% mPEG 9 × 3 × 1 13335-83-2 5050 DLG 1A 6010% mPEG  9 × 3 × 1 13335-83-5 5050 DLG 1A 60 8% mPEG 9 × 3 × 1

Example 6

Bupivacaine implants were prepared according to the procedure describedin Example 5 above. The formulation used to prepare the implants isdescribed below in Table 6. In particular, the formulation contained 50wt % bupivacaine base, 42 wt. % 5050DLG 1A, and 8 wt. % mPEG. Theinherent viscosity of the 5050DLG was 0.05-0.15 and it had an acid endgroup.

TABLE 6 % Drug Ribbon Size (mm) Polymer Polymer Load (%) Excipient (L ×W × H) 5050 DLG 1A 42 50 8% mPEG 9 × 3 × 1

The in vitro cumulative and daily release profile was tested beforesterilization using three strip implants from the formulation describedin Table 6. FIGS. 15A and 15B are in vitro graphic representations ofthe percentage cumulative release of three sterilized bupivacainestrips. As is readily apparent in these figures, each formulationreleased between 65% to 85% of the bupivacaine over 14 days with anaverage of 5%-10% of drug released every day. The average cumulativedrug release of the three strips is shown in FIG. 15B, where 75% of thedrug released in 14 days.

FIGS. 16A and 16B are in vitro graphic representations of the dailyrelease profile of the three sterilized bupivacaine strips and theircumulative average daily release in micrograms per day. As is readilyapparent in these figures, each drug depot had an initial burst effectwith a release of bupivacaine at a dose of about 3500 mcg within 2 days.After the two days, each drug depot released about 500-1000 mcg per dayuntil the drug depot was exhausted at day 14.

Example 7 In vivo Efficacy Evaluation of Bupivacaine Implants in the PigSurgical Model

Induction of Post-Operative Pain in Piglets:

Piglets were anesthetized by Isoflurane/Oxygen mixture, which wasdelivered through a face mask. A 5 cm long skin and fascia incision wasmade to the right femur at the groin keeping the muscle intact. The skinincision was closed with metal clamps. The duration of the anesthesiawas kept at less than 10 minutes. Immediately after the incision, theanimals were administered with either control or drug implants into theincisional space. Morphine (Mor) was administered subcutaneously in theanimals in a morphine group as a positive control.

Analgesia Evaluation:

The analgesic effect of bupivacaine implants was assessed using painbehavior scoring. The pain scoring system was the summation of 3 majorcategories:

-   -   1. Animal solitary performance (walking and vocalization)    -   2. Animal social behavior    -   3. The length of time in which the pigs stayed on a sling

All animals were observed at baseline (3 days prior to surgery) and at 1and 3 hours post-surgery (study day 0). Pain behavior was then assesseddaily for 4 more days (study days 1, 2, 3 and 4). The implants wereadministered into the surgical wound bed on study day 0 immediatelyright after surgery. Morphine was administered one hour prior to painassessment in animals in the morphine group (Mor).

Results:

FIG. 17 shows an in vivo efficacy evaluation of bupivacaine high dose(250 mcg loaded in the depot, designed to release 25 mcg/day)formulations and bupivacaine low dose (125 mcg loaded in the depot,designed to release 12.5 mcg/day) formulations as measured by painscores at 1 hour, 3 hours, day 1, day 2, day 3, and day 4, post-surgery.The increase in the pain behavior score reached a peak at 3 hourspost-surgery on study day 0 (control group: 7.83±0.9 points). The highmean group pain score of the control treated animals was observed alsoon study day 1. On study day 2 spontaneous recovery of pain behavior wasobserved and 4 days post-surgery the pain behavior score was notstatistically different from baseline value.

Treatment with bupivacaine implants using a high level dose waseffective in reducing pain 3 hours post-surgery and 1 day post-surgery.This effect was not dose related.

CONCLUSION

In view of the findings obtained under the conditions of this study andconfined to the in-life data, treatment with bupivacaine implants athigh levels was effective in reducing post-operative pain in pigs.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

What is claimed is:
 1. An implantable drug depot useful for reducing,preventing or treating post-operative pain in a patient in need of suchtreatment, the implantable drug depot comprising a polymer comprisingpoly(D,L-lactide-co-glycolide), a therapeutically effective amount of alocal anesthetic comprising bupivacaine or pharmaceutically acceptablesalt thereof and an excipient comprising methoxy polyethylene glycol(mPEG), the depot being implantable at a site beneath the skin of thepatient to reduce, prevent or treat post-operative pain, wherein thedrug depot is capable of releasing (i) a bolus dose of the localanesthetic or pharmaceutically acceptable salt thereof at a site beneaththe skin of the patient and (ii) a sustained release dose of aneffective amount of the local anesthetic or pharmaceutically acceptablesalt thereof over a period of at least 4 days, wherein the localanesthetic is present in an amount of about 60 wt. % of the depot, thepolymer is present in an amount of about 30% of the depot and themethoxy polyethylene glycol (mPEG) is present in an amount of about 10wt. % of the depot.
 2. The implantable drug depot according to claim 1,wherein the local anesthetic further comprises ropivacaine, mepivacaine,etidocaine, levobupivacaine, trimecaine, carticaine or articaine.
 3. Theimplantable drug depot according to claim 1, wherein the bupivacaine isin the form of a salt.
 4. The implantable drug depot according to claim1, wherein the bupivacaine is in the form of a base.
 5. The implantabledrug depot according to claim 1, wherein the polymer further comprisesone or more of poly(lactide-co-glycolide), polylactide, polyglycolide,polyorthoester, D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide,poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof.
 6. The implantable drug depot according to claim 1,wherein the polymer is capable of degrading in 30 days or less after thedrug depot is implanted at the site.
 7. The implantable drug depotaccording to claim 1, wherein the drug depot is capable of releasing thelocal anesthetic in an amount between 50 and 800 mg per day for a periodof 4 to 10 days.
 8. A method of treating or preventing post-operativepain in a patient in need of such treatment, the method comprisingadministering one or more drug depots according to claim 1 to a targettissue before, during or after surgery, wherein the drug depot iscapable of releasing an initial bolus dose of the local anesthetic orpharmaceutically acceptable salt thereof at a site beneath the skin ofthe patient followed by a sustained release dose of an effective amountof the local anesthetic or pharmaceutically acceptable salt thereof overa period of at least 4 days.
 9. The method of treating or preventingpost-operative pain according to claim 8, wherein the local anestheticfurther comprises ropivacaine, mepivacaine, etidocaine, levobupivacaine,trimecaine, carticaine or articaine.
 10. The method of treating orpreventing post-operative pain according to claim 8, wherein the drugdepot is capable of releasing about 40% to about 70% of the localanesthetic or pharmaceutically acceptable salt thereof relative to atotal amount of the local anesthetic loaded in the drug depot over aperiod of 4 to 10 days after the drug depot is administered to thetarget tissue site.
 11. The method of treating or preventingpost-operative pain according to claim 8, wherein the drug depot iscapable of releasing between 50 and 800 mg/day of the local anestheticor pharmaceutically acceptable salt thereof for a period of 4 to 10days.
 12. The method of treating or preventing post-operative painaccording to claim 8, wherein the polymer further comprises one or moreof poly(lactide-co-glycolide), polylactide, polyglycolide,polyorthoester, D-lactide, D,L-lactide, poly(D,L-lactide), L-lactide,poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof.
 13. An implantable drug depot useful for reducing,preventing or treating post-operative pain in a patient in need of suchtreatment, the implantable drug depot comprising a therapeuticallyeffective amount of bupivacaine or pharmaceutically acceptable saltthereof, a polymer comprising poly(D,L-lactide-co-glycolide) and anexcipient comprising methoxy polyethylene glycol (mPEG); wherein thedepot is implantable at a site beneath the skin of the patient toreduce, prevent or treat post-operative pain, and the depot is capableof releasing (i) about 2% to about 50% of the bupivacaine orpharmaceutically acceptable salt thereof relative to a total amount ofthe bupivacaine or pharmaceutically acceptable salt thereof loaded inthe drug depot over a first period of up to 48 hours and (ii) about 50%to about 98% of the bupivacaine or pharmaceutically acceptable saltthereof relative to a total amount of the bupivacaine orpharmaceutically acceptable salt thereof loaded in the drug depot over asubsequent period of up to 3 to 10 days, wherein the local anesthetic ispresent in an amount of about 60 wt. % of the depot, the polymer ispresent in an amount of about 30% of the depot and the methoxypolyethylene glycol (mPEG) is present in an amount of about 10 wt. % ofthe depot.
 14. The implantable drug depot according to claim 13, whereinthe polymer further comprises one or more of poly(lactide-co-glycolide),polylactide, polyglycolide, polyorthoester, D-lactide, D,L-lactide,poly(D,L-lactide), L-lactide, poly(D,L-lactide-co-caprolactone),poly(D,L-lactide-co-glycolide-co-caprolactone), polycaprolactone or acombination thereof.
 15. The implantable drug depot according to claim13, wherein the drug depot is capable of releasing between 50 and 800mg/day of bupivacaine or pharmaceutically acceptable salt thereof. 16.The implantable drug depot according to claim 13, wherein the polymer iscapable of degrading in 30 days or less after the drug depot isimplanted at the site.
 17. A method of making an implantable drug depotof claim 13, the method comprising combining a biocompatible polymer anda therapeutically effective amount of bupivacaine or pharmaceuticallyacceptable salt thereof and forming the implantable drug depot from thecombination.